Abstract
Hearing loss is a common manifestation of Hunter’s syndrome, with reported rates ranging from 67.3 to 94%. The aim is to highlight the audiological profile and pathophysiology of mixed hearing loss in individuals with hunter’s syndrome. A 7.6-year-old male child was brought to the department of audiology with a complaint of not responding to name call and regression in the speech and language skills. Detailed audiological showed severe to profound mixed hearing loss. REELS and 3DLAT results showed RLA to be 9 to 10 months and ELA to be 6 to 7 months. Owing to the progressive nature and high prevalence of hearing loss in hunter’s syndrome, this case report highlights the importance of middle ear evaluation in the pediatric hearing assessment apart from OAE and ABR. Speech- language therapy must be considered with a focus on functional communication.
Keywords: Hunter’s syndrome, Mucopolysaccharides II, Glycosaminoglycans, Auditory brainstem response, Immittance evaluation, Hearing loss, Mixed hearing loss, Speech and language delay
Introduction
Mucopolysaccharidoses is a group of genetic disorders characterized by an excessive accumulation of mucopolysaccharides or glycosaminoglycans (GAGs) in different body sites. There are several types of MPS, all of which are caused by a lack of function in the enzymes responsible for the breakdown of mucopolysaccharides, the complex carbohydrates abundant in connective tissue (Neufeld and Muenzer, 2001). The different types of MPS are MPS type I (Hurler syndrome), MPS II (Hunters syndrome), MPS III (Sanfilippo syndrome), MPS IV (Morquio syndrome), MPS VI (Maroteaux- Lamy syndrome), MPS VII (Sly syndrome), MPS IX (Natowicz Syndrome) [1].
Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient leading to mental and physical retardation [2]. Heparan and dermatan sulphate are the chemicals that accumulate in Hunter’s syndrome, while iduronate 2- sulphatase enzyme is missing. In India, the actual incidence and prevalence rates are unknown. However, according to the findings of a research conducted in the United Kingdom its incidence is 1 in 171,132 live births, or 0.584 per 100,000 [3]. However, a far higher rate of 1 in 67,500 live births was discovered in a survey of Jews in Israel, leading the authors to speculate that Hunter’s syndrome may be a Jewish condition [4]. Males constitute the majority, but female cases have been reported on occasion. Heart disease, skeletal deformities, upper respiratory tract infections, abdominal distension, developmental delays, and hearing loss are common in both phenotypes of MPS II [5].
Hearing loss is common with reported rates ranging from 67.3 to 94% in hunter’s syndrome. Hearing loss in MPS II has been described as progressive with an estimated rate of loss at 1 dbHL per year. The severity of hearing loss varies, with patients ranging from mild to profound. Patients often first experience conductive hearing loss when they are younger. In later stages, a sensorineural component may lead to eventual severe deafness [6]. Speech and language delay is seen in individuals with Hunters syndrome. Motor and verbal developmental milestones are both delayed in extreme cases. By the age of six, children reach developmental plateaus and begin to regress. Articulation and language skills will deteriorate to progressive hearing loss as well as progressive changes in the structures that support speech production. Thickened vocal folds results in a hoarse, deep vocal quality, and shallow breathing patterns may reduce volume. Unless some alternate communication system is developed, communication skills will be severely limited if tracheotomized breathing becomes necessary [7].
There is lack of literature understanding the pathophysiology of the conductive and sensorineural hearing loss in children with Hunters syndrome. Also, on single study talks about both hearing and language profiles in cases with Hunters syndrome. Hence the case report aims to highlight the audiological profile and pathophysiology of mixed hearing loss in individuals with Hunters syndrome, importance of middle ear evaluation in pediatric audiological testing protocol, importance of audiological and speech and language evaluation in individuals with Hunters syndrome.
Case Report
A 7.6-year-old male child was referred to the department of Audiology and SLP at Wenlock district hospital, Mangalore on June 30, 2022 for audiological evaluation. The parents presented with the complaint that child had frequent cold and ear infections and did not respond to name call. Informed consent was taken from the parents prior to audiological evaluation. Detailed audiological evaluation was carried out through otoscopic examination, immittance evaluation, and auditory brainstem response. The otoscopic examination was done using an otoscope and the results revealed right ear tympanic membrane appearing to be bulged and left ear tympanic membrane appearing to be retracted. Immittance evaluation was carried out using the GSI Tympstar instrument and the test included tympanometry and acoustic reflex with a probe frequency of 226 Hz and a pump rate of -800 daPa to + 600 daPa (ANSI standard). Tympanometry performed with 226 Hz probe tone indicated ‘Cs’ and ‘B’ type of tympanogram in the right and left ear respectively as shown in Table 1. The acoustic reflex findings revealed absent middle ear reflexes.
Table 1.
Results of Tympanometry
| Right ear | Left ear | |
|---|---|---|
| Peak pressure (daPa) | -145 | NP |
| Peak compliance (ml) | 0.27 | NP |
| Physical volume (cc) | 1.6 | 1.3 |
| Tympanogram | ‘Cs’ | ‘B’ |
Auditory Brainstem Response (ABR) evaluation was carried out using the Neuro-Audio software by Neurosoft, Russia. ABR protocol used for hearing evaluation are shown in Table 2. The recommended electrodes montage was followed to record ABR waveforms with the non-inverting (+) electrode on the vertex, inverting (-) electrode on the test ear, and ground electrode on the non-test ear. Auditory brainstem response (ABR) evaluation under sedation showed no significant peaks at 90 dBnHL (Fig. 1) indicating severe to profound mixed hearing loss.
Table 2.
ABR protocol
| Stimulus | Clicks |
|---|---|
| Intensity | 90dBnHL |
| Polarity | Alternating |
| Transducer | TDH 39 P |
| Filter settings | 30- 3000 Hz |
| Analysis time | 15ms |
| Rate | 30.1/s |
| Number of stimuli | 2000 |
| Stimulus presentation | Monoaural |
Fig. 1.
Auditory Brainstem Response waveform of the 7.6-year-old male child with Hunters syndrome
With respect to speech and language, the parents presented with the complaint of regression in the speech and language skills after 2 years of age. The child presents with a family history of schizophrenia in the maternal side and hysteria in the paternal side of the family. The mother’s and the father’s age during the birth of the child was 29 years and 38 years respectively. The child has a younger brother aged 2.5 years and is reported to have similar issues. The mother has a history of miscarriage 3 years before the child was born (in 2011), high BP in her last trimester of her pregnancy. The child was born full-term through a C-section delivery. The child weighed 3.95 kg. The child had frequent cold, diarrhea and ear infections. The child was under homeopathy medicines for growth. The child had delayed motor development and had not yet achieved toilet control. The child also has delayed language milestones and did not combine words during speech. The child had poor social development, had neither social smile nor group play. The child was engaged in solo play only and exhibited behavioral issues. Poor vegetative skills and prolonged feeding duration was observed. Speech and language profile of the child exhibited poor pre-linguistic skills (eye contact, attention to speech, joint attention, attention span, imitation, sitting behavior), no meaningful utterances. The child recognizes few objects by function, expresses his needs by vocalization.
Oral peripheral speech mechanism examination presented structurally and functionally inadequate articulators, marcoglossia and missing teeth. The standardized tests administered were Receptive Expressive Emergent Language Scale (REELS) and 3-Dimensional Language Acquisition Test (3D LAT). Both the results showed a delay in receptive (9 to 10 months) and expressive (6 to 7 months) language age. The child was provisionally diagnosed as Developmental language disorder secondary to intellectual disability and Hearing impairment.
Discussion
The pathophysiology of the persistent conductive and sensorineural hearing loss is not well understood in the literature. Preliminary evidence reported several malformations in the temporal bone in individuals with hunter’s syndrome which may be the cause for hearing loss. Due to the accumulation of Glycosaminoglycans in the middle ear and eustachian tube, anomalies like chronic otitis media, dysostosis of ossicular chain, tympanic membrane scarring, tympanomastoid abnormalities are reported which accounts for the conductive portion of the hearing loss [8]. Nature and origin of sensorineural hearing loss is not well understood by the literature. There are few studies showing an association between chronic otitis media and sensorineural hearing loss. Thus, recurrent otitis media does account for the sensorineural portion of hearing loss [9]. Reported anomalies includes the absence of malleoincudal joint, disintegrated stria vascularis, widespread collagen damage, haemorrhages in the middle ear, which explains the presence of mixed hearing loss in individuals with hunter’s syndrome [9]. Other studies have reported deposition of glycosaminoglycans (GAGs) in the eustachian tube and middle ear could be the cause for frequent middle ear infections. Glycosaminoglycans (GAGs), also known as mucopolysaccharides, they are negatively-charged polysaccharide compounds. They are included in processes like regulation of cell growth and proliferation, promotion of cell adhesion, anticoagulation, and wound repair among many more. Pathophysiological processes related to Glycosaminoglycans (GAGs) are very broad in range due to their ubiquitous nature in the body. Glycosaminoglycans (GAGs) are important to the infectious processes of various viral, bacterial, fungal, and parasitic pathogens. The presence of Glycosaminoglycans (GAGs) facilitates microorganism growth in the middle ear [10]. Severe language impairment appears to result from profound intellectual disability rather than from hearing loss. Most patients with the intermediate or severe form exhibited severe speech delay by more than 2 years. However, in patients with mild form and normal intelligence, hearing loss was found to influence the speech ability. Mild speech delay occurred in patients with mild hearing loss. Although grommet insertion may improve hearing in these individuals, language and cognitive abilities are so delayed that they cannot be influenced by hearing improvement [11].
Owing to the progressive nature and high prevalence of hearing loss in hunter’s syndrome, this case report highlights the importance of frequent audiological evaluation in individuals with hunter’s syndrome. It also highlights the importance of middle ear evaluation in paediatric hearing assessment apart from otoacoustic emission (OAE) and auditory brainstem response (ABR). Constant vigilance and aggressive ontological and audiological management are required for individuals with hunter’s syndrome since they are at risk for middle ear effusion and conductive hearing loss. Follow-up evaluation after the treatment of the middle ear condition is very crucial since middle ear disturbances may mask a coexisting sensorineural hearing loss and to rule out sensorineural hearing impairment. Clinicians should not delay considering hearing aids for individuals with hunter’s syndrome, if good hearing cannot be maintained. Speech-language therapy must be considered for individuals with hunter’s syndrome with a focus on functional communication skills. Augmentative and alternative communication methods can be used. As gross and fine motor skills deteriorate, and oromotor are poor in these individuals, the child may have feeding and swallowing issues as well. In such cases, speech language pathologists will have to help with feeding and swallowing issues of the child. Along with this, an effective counselling is essential to make the family/ caregivers understand the condition and have realistic expectations.
Funding
The author(s) received no financial support for the research.
Declarations
Competing Interest
No potential conflict of interest was reported by the authors.
All procedures performed in the study were in accordance with the ethical standards of the institutional research and ethics committee.
Footnotes
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References
- 1.Lukacs Z (2008) Mucopolysaccharides, in Laboratory guide to the methods in biochemical genetics. Springer, pp 287–324
- 2.Scarpa M (2018) Mucopolysaccharidosis type II Synonyms: Hunter Syndrome, Iduronate-2-Sulfatase Deficiency, MPS II. GeneReviews § [Internet]
- 3.Archer IM, et al. Carrier detection in Hunter syndrome. Am J Med Genet. 1983;16(1):61–69. doi: 10.1002/ajmg.1320160111. [DOI] [PubMed] [Google Scholar]
- 4.Schaap T, Bach G. Incidence of mucopolysaccharidoses in Israel: is Hunter disease a “Jewish disease. Hum Genet. 1980;56:221–223. doi: 10.1007/BF00295699. [DOI] [PubMed] [Google Scholar]
- 5.Martin R, et al. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome) Pediatrics. 2008;121(2):e377–e386. doi: 10.1542/peds.2007-1350. [DOI] [PubMed] [Google Scholar]
- 6.Wolfberg J, et al. Hearing loss in mucopolysaccharidoses: current knowledge and future directions. Diagnostics. 2020;10(8):554. doi: 10.3390/diagnostics10080554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Alpern CS. Hunter’s syndrome and its management in a Public School setting. Lang Speech Hear Serv Sch. 1992;23(2):102–106. doi: 10.1044/0161-1461.2302.102. [DOI] [Google Scholar]
- 8.Gökdoğan Ç, et al. Audiologic evaluations of children with mucopolysaccharidosis. Braz J Otorhinolaryngol. 2016;82:281–284. doi: 10.1016/j.bjorl.2015.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Cho Y-S, et al. Otologic manifestations of Hunter syndrome and their relationship with speech development. Audiol Neurotology. 2008;13(3):206–212. doi: 10.1159/000113511. [DOI] [PubMed] [Google Scholar]
- 10.Casale C, Crane J. J, Biochemistry, Glycosaminoglycans, StatPearls. Treasure Island (FL): StatPearl s Publishing; 2022. [PubMed] [Google Scholar]
- 11.Wallace SP, Prutting CA, Gerber SE. Degeneration of speech, language, and hearing in a patient with mucopolysaccharidosis VII. Int J Pediatr Otorhinolaryngol. 1990;19(2):97–107. doi: 10.1016/0165-5876(90)90215-D. [DOI] [PubMed] [Google Scholar]