**3. Results**

#### **3.1. Audiological workup**

Some degree of hearing impairment was present in 61 children (74.4%) of the whole cohort of 82 young patients (up to 14 years of age). A total of 21 children (25.6%) were normally hearing. Approximately the same rate of hearing impairment was found in 36 children of the cohort 47 under 6 years of age (76.6%) rather than at older ages; it was sensorineural or mixed in almost half of the ears (47.44%) and purely conductive in about one-third (27.02%). Hearing loss was always symmetrical in the two ears (within 10 dB differences between ears at same frequencies).

identifiable response was obtained: in 3 of them, the hearing threshold was severe enough to explain the absence of the response; in 4 cases a retrocochlear involvement was suspected.

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The relationship between the MPS types and the ABR findings is shown in **Table 3**: all children with MPS III demonstrated an altered ABR; the greatest majority of MPS II also proved pathological, as well as half of the MPS I. None of the patients affected by MPS IVA and VI

According to ABR response, the hearing loss was of the "cochlear" type in 83.3, 77.8 and 85.7% of MPS I, MPS II and MPS III, respectively. One case of absent wave I plus absent or delayed wave III and V were observed in MPS I and III, similarly to two cases of MPS II. In no instance an isolated delay of wave V was observed, thus excluding purely "central" site of lesions.

In most MPS children with hearing loss, the hearing threshold derived from the ABRs wave V thresholds ranged between 70 and 90 dB SPL (40–60 dB HL) with an average of 85.62 dB SPL.

Among the 37 MRI, 14 (37.84%) were normal, whereas 23 (62.16%) were pathologic. The most frequent abnormal neuroradiological findings were represented by dilated perivascular spaces (due to extracellular storage of GAGs) in = 12 (32.43%); dilated ventricular cavities n = 15 (40.54%); demyelinated and gliotic areas n = 9 (24.32%). The frequent observation of a

We reviewed all MRI with a particular attention on the middle and inner ear findings, although imaging was a standard brain study, not addressing the ear morphology per se. We ascertained five cases of globose internal auditory canal (IAC), and one case of cystic cochlear

5 (46.5%) 6 (54.5%) 5 1 0

1 (10%) 9 (90%) 7 2 0

0 7 (100%) 6 1 0

14 0 0 0 0

5 0 0 0 0

Total 25/47 (53.2%) 22/47 (46.8%) 18 (81.8%) 4 (8.5%) 0

**Table 3.** Distribution of abnormal ABR findings according to MPS type (n = 47).

**Absent wave I or delayed wave I-III-V (cochlear hearing loss (IPI within normal range)**

**Absent wave I and absent or delayed wave III**  **Delayed wave V only**

**and V**

Overall, a retrocochlear involvement was likely in 8.5% of MPS children.

J-shaped sella was considered a non-pathological anatomical variant.

**Abnormal ABR**

revealed abnormal ABR tracings.

**3.2. Neuroimaging**

**MPS type Normal latencies (all** 

MPS-I (n = 11)

MPS-II (n = 10)

MPS III (n = 7)

MPS IV (n = 14)

MPS VI (n = 5)

**peaks recognizable)**

Five children presented with normal hearing at admission (mean PTA <20 dB HL bilaterally). The average AC threshold in the "C" group was 44 dB HL with an air-bone gap (ABG) of 21 dB HL; the "S" group showed an AC threshold PTA = 62.5 dB HL with an ABG of 2.3 dB HL. In 7 children (18.9%), the tympanograms were normal (type "A") at the time of the initial assessment and contralateral stapedial reflexes showed a normal threshold and morphology; in the other 30 (81.0%) they were pathological in both ears (Type "B" n = 14; type "C" n = 16).

Transient evoked otoacoustic emissions (TEOAE) were absent bilaterally in all children with a hearing threshold worse than 25 dB HL; normal otoacoustic emission responses were obtained in 9 out of 10 normally hearing ears.

Normative latencies for the three main ABR peaks in normally hearing children of different ages are reported in **Table 2**, and compared to those obtained in the MPS cohort stratified in the same three age groups. Statistical analysis was performed by means of Wilcoxon signed rank test; p < 0.005 was considered statistically significant.

In MPS children, ABRs to click stimuli were morphologically normal with peak latencies within normal limits (avg ± 1 SD) in 25 out of 47 subjects (53.2%), whereas 22 tracings showed abnormalities (46.8%). A typical waveform with the 3 main peaks was recognizable or only wave I was missing in 18 of these 22 cases at a stimulus intensity of 90 dB HL, but the amplitudes were reduced and all the latencies delayed ("cochlear" site of lesion); in 7 children no


Latency values expressed in ms. Wilcoxon signed rank test, statistical significance at p < 0.005.

**Table 2.** ABR's absolute wave latencies (ms) and inter-peak intervals (IPI, ms) in the MPS cohort stratified by age and compared to those obtained in the normally hearing age-matched children (control groups Norm 1-2-3).

identifiable response was obtained: in 3 of them, the hearing threshold was severe enough to explain the absence of the response; in 4 cases a retrocochlear involvement was suspected. Overall, a retrocochlear involvement was likely in 8.5% of MPS children.

The relationship between the MPS types and the ABR findings is shown in **Table 3**: all children with MPS III demonstrated an altered ABR; the greatest majority of MPS II also proved pathological, as well as half of the MPS I. None of the patients affected by MPS IVA and VI revealed abnormal ABR tracings.

According to ABR response, the hearing loss was of the "cochlear" type in 83.3, 77.8 and 85.7% of MPS I, MPS II and MPS III, respectively. One case of absent wave I plus absent or delayed wave III and V were observed in MPS I and III, similarly to two cases of MPS II. In no instance an isolated delay of wave V was observed, thus excluding purely "central" site of lesions.

In most MPS children with hearing loss, the hearing threshold derived from the ABRs wave V thresholds ranged between 70 and 90 dB SPL (40–60 dB HL) with an average of 85.62 dB SPL.

#### **3.2. Neuroimaging**

**3. Results**

60 An Excursus into Hearing Loss

**Wave latencies** **MPS 12 mo**

**3.1. Audiological workup**

obtained in 9 out of 10 normally hearing ears.

**Norm 1**

rank test; p < 0.005 was considered statistically significant.

**p MPS** 

Latency values expressed in ms. Wilcoxon signed rank test, statistical significance at p < 0.005.

compared to those obtained in the normally hearing age-matched children (control groups Norm 1-2-3).

**18–24 mo**

Wave I 1.89 ± 0.21 1.62 ± 0.31 0.046 2.01 ± 0.18 1.88 ± 0.26 n.s. 2.18 ± 0.29 1.99 ± 0.48 n.s. Wave III 4.30 ± 0.12 4.00 ± 0.34 n.s. 4.51 ± 0.25 4.12 ± 0.11 0.0001 4.45 ± 0.22 4.17 ± 0.3 0.0001 Wave V 6.39 ± 0.18 5.92 ± 0.25 0.0001 7.02 ± 0.2 5.96 ± 0.28 0.0001 7.39 ± 0.26 5.98 ± 0.11 0.0001 IPI I–III 2.40 ± 0.22 2.37 ± 0.21 n.s. 2.50 ± 0.31 2.24 ± 0.25 n.s. 2.27 ± 0.22 2.18 ± 0.21 n.s. IPI I–V 4.33 ± 0.1 4.31 ± 0.16 n.s. 5.01 ± 0.18 4.98 ± 0.16 n.s. 5.21 ± 0.1 4.0 ± 0.26 0.0001

**Table 2.** ABR's absolute wave latencies (ms) and inter-peak intervals (IPI, ms) in the MPS cohort stratified by age and

Some degree of hearing impairment was present in 61 children (74.4%) of the whole cohort of 82 young patients (up to 14 years of age). A total of 21 children (25.6%) were normally hearing. Approximately the same rate of hearing impairment was found in 36 children of the cohort 47 under 6 years of age (76.6%) rather than at older ages; it was sensorineural or mixed in almost half of the ears (47.44%) and purely conductive in about one-third (27.02%). Hearing loss was always symmetrical in the two ears (within 10 dB differences between ears at same frequencies). Five children presented with normal hearing at admission (mean PTA <20 dB HL bilaterally). The average AC threshold in the "C" group was 44 dB HL with an air-bone gap (ABG) of 21 dB HL; the "S" group showed an AC threshold PTA = 62.5 dB HL with an ABG of 2.3 dB HL. In 7 children (18.9%), the tympanograms were normal (type "A") at the time of the initial assessment and contralateral stapedial reflexes showed a normal threshold and morphology; in the other 30 (81.0%) they were pathological in both ears (Type "B" n = 14; type "C" n = 16). Transient evoked otoacoustic emissions (TEOAE) were absent bilaterally in all children with a hearing threshold worse than 25 dB HL; normal otoacoustic emission responses were

Normative latencies for the three main ABR peaks in normally hearing children of different ages are reported in **Table 2**, and compared to those obtained in the MPS cohort stratified in the same three age groups. Statistical analysis was performed by means of Wilcoxon signed

In MPS children, ABRs to click stimuli were morphologically normal with peak latencies within normal limits (avg ± 1 SD) in 25 out of 47 subjects (53.2%), whereas 22 tracings showed abnormalities (46.8%). A typical waveform with the 3 main peaks was recognizable or only wave I was missing in 18 of these 22 cases at a stimulus intensity of 90 dB HL, but the amplitudes were reduced and all the latencies delayed ("cochlear" site of lesion); in 7 children no

> **Norm 2**

**p MPS 2–6 ys** **Norm 3**

**p**

Among the 37 MRI, 14 (37.84%) were normal, whereas 23 (62.16%) were pathologic. The most frequent abnormal neuroradiological findings were represented by dilated perivascular spaces (due to extracellular storage of GAGs) in = 12 (32.43%); dilated ventricular cavities n = 15 (40.54%); demyelinated and gliotic areas n = 9 (24.32%). The frequent observation of a J-shaped sella was considered a non-pathological anatomical variant.

We reviewed all MRI with a particular attention on the middle and inner ear findings, although imaging was a standard brain study, not addressing the ear morphology per se. We ascertained five cases of globose internal auditory canal (IAC), and one case of cystic cochlear


**Table 3.** Distribution of abnormal ABR findings according to MPS type (n = 47).

(81.08%) were between 2 and 6 years old. By contrasting the rate of pathological ABR and the MRI findings according to the age layers we obtained the outcomes illustrated in **Table 4**. Noticeably, the majority of children underwent an ABR after 2 years of age, when, theoretically, the physiological maturation of the central auditory pathways should be completed.

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The MPSs are a group of monogenic disorders due to lysosomal storage of glycosaminoglycans (GAGs), previously called mucopolysaccharides [14]. The deficiency of one of the enzymes participating in the GAGs degradation pathway causes progressive storage in the lysosomes and cytoplasm, leading to cell swelling and multiple organs dysfunction. The damage is both direct or by activation of secondary and tertiary pathways among which a role is played by inflammation. [15] All MPSs have an autosomal recessive transmission with the exception of

The incidence of MPSs as a group is reported between 1:25,000 and 1:45,000 [17]. At present, 11 different enzyme deficiencies are involved in MPSs producing 7 distinct clinical phenotypes [14] (**Table 1**). Depending on the enzyme deficiency, the catabolism of dermatan sulfate, heparin sulfate, keratin sulfate, chondroitin sulfate, or hyaluronan may be impaired, singu-

MPSs virtually affect all organs and tissues and show a progressive worsening with time. Diagnosis is suspected clinically on the basis of rather constant physical appearance (signs can be subtle or overt) such as: coarse facial features; short stature; "claw hand" and/or joint stiffness or ligamentous laxity (seen in MPS VI); corneal clouding (from very mild to severe), retinopathy, glaucoma; chronic nasal congestion, noisy breathing; abdominal protuberance owing to liver and spleen enlargement; spinal deformity (gibbus, scoliosis, kyphosis, lordosis); abnormal gait (e.g., toe walking); hearing deficits and brain involvement with progressive cognitive delay. In MPS III and II, mental retardation at 2–3 years may be the only, or most evident, presenting sign. Heart failure and severe valve disease in the first year of life are reported as the first presenting symptom in the *severe* forms [18–20]. In these patients, quality

The *attenuated* forms have widely variable clinical presentations with different presenting signs at different ages, often one or few organs only clinically manifest the disease [2, 3]. In these milder forms the progression of signs and symptoms is much slower than in the severe ones. These patients may have a presentation apparently limited to one organ only and are often seen by a specialist for years before reaching the diagnosis [2, 3], that is usually accom-

Currently, specific treatments such as hematopoietic stem cell transplantation in selected cases of severe MPS I and enzyme replacement therapy for MPS I, II, IV and VI are available [23]. These treatments are able to improve the clinical course of the disease if started early. This brings along the responsibility for the clinician to recognize these diseases at the first

signs to allow access to treatment before a severe damage has been established.

MPS type II (Hunter syndrome) which is X-linked [16].

of life and life span are generally substantially reduced [21, 22].

plished by means of biochemical, enzymatic and molecular tests.

**4. Discussion**

larly or in combination.

apex and dilated vestibule, which is shown in **Figure 3**. All detected anomalies were bilateral except for the dilated vestibule (right ear, pt. # 14). The middle ear pathological findings consisted in 15 cases of sero-mucinous effusion in the mastoid cells and in the tympanic cavity, 9 bilateral and 4 unilateral (always the right side). In no instance an enlarged vestibular aqueduct was detected. Similarly, no pathological conditions were identified along the central auditory pathways in any young MPS patients.

We further stratified the 37 MR+ patients in 3 subgroups related to age: 5 (13.51%) patients were under 1 years old, only 2 children (5.4%) were between 1 and 2 years old and 30 children


**Table 4.** Incidence of pathological ABRs and MRIs at different ages in the subgroup of 37 MPS patients who underwent both investigations.

(81.08%) were between 2 and 6 years old. By contrasting the rate of pathological ABR and the MRI findings according to the age layers we obtained the outcomes illustrated in **Table 4**. Noticeably, the majority of children underwent an ABR after 2 years of age, when, theoretically, the physiological maturation of the central auditory pathways should be completed.
