**2. Materials and methods**

MPS disorders have an overall incidence reported of 1.53 per 100,000 live births ranging from 1 in 150,000 to as high as 1 in 10,000 live births [1]. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%,

The majority are characterized by an autosomal recessive pattern (except for X-linked MPS II type). The deficiency of one of the enzymes participating in the GAGs degradation pathway causes progressive storage in the lysosomes, leading to cellular, tissues and organs dysfunction. The damage is both direct or by activation of secondary and tertiary pathways among

Nowadays 11 different enzyme deficiencies are known to be involved in MPSs producing seven distinct clinical phenotypes. In contrast to a recent past when there was only palliative treatment for these diseases, now many specific treatments like hematopoietic stem cell transplantation (HSCT) in selected cases (severe MPS I) and enzyme replacement therapy (ERT)

MPSs can manifest as severe or attenuated clinical picture. The "severe" forms frequently appear in the first 2–3 years of life with skeletal abnormalities often accompanied by dysmorphic facies, organomegaly, multiple hernias (inguinal, umbilical), abnormally frequent and severe upper airways infections, otitis media and chronic rhinitis. In the "attenuated" forms of the disease instead, the progression of signs and symptoms is much

These patients may show the prevalent involvement of a single organ and are often seen by

The most frequent signs of presentation are cardiac valve disease, eye disease, hearing loss,

In both forms, the disease invariably progresses with time. MRI of the brain and cervical spine

Surgery to stabilize the spine by posterior fusion can be life-saving. Both central and peripheral nervous systems are affected in the MPSs. Prominent perivascular spaces, hydrocepha-

The communicating hydrocephalus that occurs in MPSs is usually slowly progressive, with mild or absent clinical symptoms. Corneal clouding in MPS I, IV, VI and VII may lead to significant visual disability. Glaucoma and cataracts have been reported in MPS I and MPS VI

In the ENT field, these patients often present obstructive sleep apnea/hypopnea (OSAHS), noisy breathing, upper respiratory tract infections, chronic rhinitis, frequent middle ear infections and mixed (conductive + sensorineural) hearing loss. The conductive component is explained by Eustachian tube obstruction or insufficiency by macroglossia, pharyngeal and soft palate mucosal swelling, hyperplasia of adenoids and tonsils. Occasionally, congenital deformities

one or two specialists for years before reaching the diagnosis [2, 3].

carpal tunnel syndrome and functional limitation of major joints [4–6].

lus, brain atrophy, gliosis and white matter changes are common [8, 9].

is recommended at the time of diagnosis and at regular intervals thereafter [7].

respectively.

56 An Excursus into Hearing Loss

slower [2, 3].

which a role is played by inflammation.

for MPS I, II, IV and VI are available.

and in MPS III and IV respectively [10].

A retrospective chart review was undertaken to document the otological clinical features and the hearing status of a group of 82 children affected by MPS who were consecutively admitted at the Department of Pediatrics of the San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy, for diagnostic purposes. The young patients were included in the study at the end of the diagnostic process, when the disease had been already characterized by its enzymatic and genetic substrate. Thus, the diagnosis was definite in all cases. We then selected to restrict the investigation to a subgroup of 47 younger children, aged less than 6 years, in order to define audiological profiles with an early prognostic value and early treatment.

We classified the 47 children according to the known MPS types (**Table 1**).

All children underwent an ENT examination during their in-hospital admission, including fiberoptic endoscopy of the upper airways and otomicroscopy. The audiological workup included:


Criteria for labeling a response as "abnormal" were the following:


A test/retest procedure was applied at 120 dB SPL stimulation and at the wave V threshold tracing.

A control group of 20 normally hearing children aged 1 year (*normative 1*), 20 children aged 18–24 months *(normative 2*) and 20 aged 3–6 years (*normative 3*) provided the ABR waves latencies normative data.

Therefore, we selected to restrict the investigation to a subgroup of younger children, aged less than 6 years. A full set of audiological data was then gathered for these 47 younger children; among them, 37 (80.43%) underwent also an MRI of the brain and ear. It was therefore possible to cross-check the outcomes of the hearing test and neuroradiological imaging in this subgroup of 37 children. They were 21 males and 16 females with a median age at admission of 3.2 years, ranging between 12 months and 6 years. **Figure 1** shows the flowchart of the study protocol.

In the majority of cases the MRIs of the brain and ear were performed under slight sedation (infants, toddlers and uncooperative children). The MRIs were obtained by a basic protocol including axial, coronal and sagittal 3D–Steady-State Free Procession sequence (SSFP), T1-weighted Fast Spin-Echo (FSE) sequence, and T2-weighted 3D Fluid Attenuated Inversion Recovery (FLAIR) sequence. MRI scans were extended from top of the skull to C7. No intravenous injection of contrast medium was applied as a standard procedure. An expert senior Neuroradiologist categorized the findings according to the three most prevalent patterns: (a) dilated perivascular spaces; (b) dilated ventricular cavities; (c) demyelinated and gliotic areas. After establishing an audiological diagnosis in terms of presence and type of hearing loss (conductive, mixed, sensorineural cochlear or retrocochlear), degree of loss, laterality, and checking the eardrum morphology at otomicroscopy, these data were contrasted with the

Characterization of Hearing Loss in Children with Mucopolysaccharidosis

http://dx.doi.org/10.5772/intechopen.74196

59

**Figure 1.** Flowchart showing the young patients' distribution according to the tests performed in the current study.

Children were divided in two groups according to the type of hearing loss: "C" = purely con-

**Figure 2.** Mean hearing thresholds levels in the "mixed" (left panel) and in the "sensorineural" hearing loss group (right

ductive; "S" = sensorineural or mixed that is reported in **Figure 2**.

MRI findings.

panel). n = 47.


**Table 1.** Clinical types of mucopolysaccharidosis (MPSs) with their underlying enzyme deficiency, accumulated substrate, and relative incidence.

Characterization of Hearing Loss in Children with Mucopolysaccharidosis http://dx.doi.org/10.5772/intechopen.74196 59

• Increased interpeak latency (IPI) compared with the normative data

A test/retest procedure was applied at 120 dB SPL stimulation and at the wave V threshold

A control group of 20 normally hearing children aged 1 year (*normative 1*), 20 children aged 18–24 months *(normative 2*) and 20 aged 3–6 years (*normative 3*) provided the ABR waves laten-

Therefore, we selected to restrict the investigation to a subgroup of younger children, aged less than 6 years. A full set of audiological data was then gathered for these 47 younger children; among them, 37 (80.43%) underwent also an MRI of the brain and ear. It was therefore possible to cross-check the outcomes of the hearing test and neuroradiological imaging in this subgroup of 37 children. They were 21 males and 16 females with a median age at admission of 3.2 years, ranging between 12 months and 6 years. **Figure 1** shows the flowchart of the

In the majority of cases the MRIs of the brain and ear were performed under slight sedation (infants, toddlers and uncooperative children). The MRIs were obtained by a basic protocol

11 α-L-Iduronidase Dermatan sulfate,

Acetyl-CoA:α-glucosamide N-acetyltransferase

MPS-IVB (Morquio B) Beta-galactoidase Keratan sulfate 1:130,000

MPS-II (Hunter) 10 Iduronate-2-sulfatase Dermatan sulfate,

MPS-IVA (Morquio A) 14 Galactose-6-sulfatase Keratan sulfate,

**Defective enzyme GAG storage** 

7 Heparan N-sulfatase Heparan sulfate 1:92,000

0 N-Acetylglucosamine-6-sulfatase Heparan sulfate 1:1,000,000

5 Arylsulfatase B Dermatan sulfate 1:120,000

**Table 1.** Clinical types of mucopolysaccharidosis (MPSs) with their underlying enzyme deficiency, accumulated

N-Acetyl-α-glucosaminidase Heparan sulfate 1:157,000

**material**

heparan sulfate

heparan sulfate

Heparan sulfate 1:714,000

chondroitin-6-sulfate

**Estimated incidence**

1:84,000

1:196,000

1:131,000

• Interaural latency difference greater than 0.20 ms

tracing.

cies normative data.

58 An Excursus into Hearing Loss

study protocol.

MPS-I (Hurler, Hurler/Scheie Scheie)

MPS-IIIa (Sanfilippo

MPS-IIIb (Sanfilippo

MPS-IIIc (Sanfilippo

MPS-IIId (Sanfilippo

substrate, and relative incidence.

A)

B)

C)

D)

MPS-VI (Maroteaux-Lamy)

**Disease Number of** 

**observed cases**

**Figure 1.** Flowchart showing the young patients' distribution according to the tests performed in the current study.

including axial, coronal and sagittal 3D–Steady-State Free Procession sequence (SSFP), T1-weighted Fast Spin-Echo (FSE) sequence, and T2-weighted 3D Fluid Attenuated Inversion Recovery (FLAIR) sequence. MRI scans were extended from top of the skull to C7. No intravenous injection of contrast medium was applied as a standard procedure. An expert senior Neuroradiologist categorized the findings according to the three most prevalent patterns: (a) dilated perivascular spaces; (b) dilated ventricular cavities; (c) demyelinated and gliotic areas.

After establishing an audiological diagnosis in terms of presence and type of hearing loss (conductive, mixed, sensorineural cochlear or retrocochlear), degree of loss, laterality, and checking the eardrum morphology at otomicroscopy, these data were contrasted with the MRI findings.

Children were divided in two groups according to the type of hearing loss: "C" = purely conductive; "S" = sensorineural or mixed that is reported in **Figure 2**.

**Figure 2.** Mean hearing thresholds levels in the "mixed" (left panel) and in the "sensorineural" hearing loss group (right panel). n = 47.
