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Dysplasia of the cerebellum in Waardenburg syndrome: Outcomes following cochlear implantation
International Journal of Pediatric Otorhinolaryngology 74 (2010) 93–96
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Dysplasia of the cerebellum in Waardenburg syndrome: Outcomes following cochlear implantation Lisa Kaufmann a, Todd B. Sauter b,c, Daniel J. Lee d,* a
Charite´ – Universita¨tsmedizin Berlin, Germany Department of Audiology, University of Massachusetts Medical School, Worcester, MA, USA c Department of Otolaryngology, University of Massachusetts Medical School, Worcester, MA, USA d Department of Otology and Laryngology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 July 2009 Received in revised form 7 October 2009 Accepted 8 October 2009 Available online 18 November 2009
This study provides the first description of isolated cerebellar dysplasia associated with Waardenburg syndrome (WS) and includes a review of cochlear implant outcomes in 42 WS patients. A 1-year-old male infant presented with speech delay, iris heterochromia, profound hearing loss, and an asymmetric, underdeveloped right occipital skull on CT imaging. Brain MRI demonstrated a hypoplastic right cerebellum, no hydrocephalus, normal auditory nerves and brainstem. He underwent successful bilateral sequential cochlear implantation. Cochlear implants remain a reasonable habilitative option for WS patients with congenital deafness, including those with cerebellar abnormalities. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Waardenburg syndrome Cochlear implant Cerebellar dysplasia
1. Introduction Waardenburg syndrome (WS) is a rare congenital disorder seen in 1/50,000 live births [1] and was first described by Waardenburg in 1951 [2]. The syndrome is regarded as a neurocristopathy resulting from an abnormal migration of the neural crest-derived cells [1]. There is genetic heterogeneity in WS and mutations involving at least eight genetic loci have been identified that result in four clinical subtypes [3]. The mode of inheritance depends on the type of WS (Table 1). Common features of WS include a hyperplastic, broad, and high nasal root, hyperplasia of the medial portions of the eyebrows, iris heterochromia, congenital deafness or unilateral hearing loss, and circumscribed albinism of the frontal hair [2]. Type 3, or Klein–Waardenburg syndrome, also presents with hypoplastic muscles and contractures of the upper limbs [4]. Type 4 (also known as Shah–Waardenburg syndrome) includes Hirschsprung’s disease and some of these patients have mental retardation [5]. Dystopia canthorum (telecanthus) is only seen in types 1 and 3 [4]. The sensorineural hearing loss seen in WS has been associated with a defect of the intermediate layer of the stria vascularis in the cochlea as a consequence of abnormal neural crest cell migration [3]. Hearing loss is found in about 20–55% of WS patients and this
* Corresponding author. Tel.: +1 617 573 3130; fax: +1 617 573 3914. E-mail addresses: [email protected], [email protected] (D.J. Lee). 0165-5876/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2009.10.007
syndrome accounts for about 2% of children with congenital deafness [6]. Structural abnormalities of the CNS are rare in WS and isolated dysplasia of the cerebellum in WS has not been previously reported. 2. Case presentation Our patient is a 1-year-old otherwise healthy male infant, the child of recent African immigrants, who presented to our office for a second opinion because of a concern of speech delay. The infant was the product of a fullterm pregnancy and uncomplicated delivery, but failed his first newborn hearing screening. An outside birth center re-screen using automated auditory brainstem response (AABR) apparently yielded a pass result for both ears. The parents denied a history of ear infections or trauma and the child had not been treated with any ototoxic medication. There was no history of gastrointestinal distress and he was thriving without difficulty. The exam was notable for brilliant sapphire eyes with iris heterochromia (Fig. 1). The child was healthy appearing, had normal facies, an unremarkable head and neck examination, and no other pigmentary abnormalities. Vestibular function and intelligence could not be assessed subjectively because the patient was not yet ambulatory and of very young age. Pure-tone thresholds were assessed using visual reinforcement audiometry techniques via ER-3A insert earphones (unaided) and in the sound field (aided) and revealed a severe to profound sensorineural
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Table 1 Subtypes of Waardenburg syndrome [4,5,6,18]. Waardenburg syndrome
Type 1
Type 2
Type 3 (Klein–WS)
Type 4 (Shah–WS)
Inheritance Gene
Autosomal dominant PAX3
Autosomal dominant/digenic MITF
Autosomal dominant PAX3
Autosomal dominant/recessive SOX10
Hearing loss Dystopia canthorum Other craniofacial abnormalities Pigmentary abnormalities Musculoskeletal abnormalities Hirschsprung´s disease Mental retardation
Yes Yes Yes Yes No No No
Yes No Yes Yes No No No
Yes Yes Yes Yes Yes No No
Yes No Yes Yes No Yes Yes
Fig. 1. Iris heterochromia. Upper panel: isohypochromia of the right iris and partial (or sectoral) heterochromia of the left eye in this child of African descent. He had a normal interpupillary distance and no dystopia canthorum (telecanthus).
hearing loss that was confirmed by comprehensive ABR testing at our facility. Tympanometry was normal bilaterally and distortion product otoacoustic emissions were absent. A radiologic evaluation included temporal bone computed tomography (CT) that demonstrated normal bony cochlear and vestibular development and an asymmetric occipital skull (Fig. 2C). Magnetic resonance imaging (MRI) of the head showed dysplasia of the cerebellum (Fig. 2A and B). Specifically, the caudal aspect of the right cerebellar hemisphere was smaller compared with the left side. The vermis appeared to be fused with the left cerebellum and was separated from the right side by a cleft that ended in the fourth ventricle. The fourth ventricle was otherwise normal in size and hydrocephalus was not seen. The brainstem was shifted slightly to the right side but the auditory nerve, root entry zone and cochlear nucleus region were grossly normal. The parents refused genetic testing. Our patient has two siblings, age 7 and 11, who are in good health with no history of hearing loss or other signs of a genetic syndrome. There was no family history of hearing loss except for one aunt with hearing loss that was felt to be secondary to measles. A diagnosis of WS type 2 was given to this child.
Fig. 3. Audiogram demonstrating pre-operative bilateral profound hearing loss, as well as aided thresholds in the borderline normal range when using right cochlear implant (CR).
The patient underwent uneventful cochlear implantation of the right ear with a Nucleus Freedom device (Cochlear Corporation) at age 17 months. The surgical anatomy was normal. A full insertion was achieved using the off-stylet technique. Intraoperative neural response telemetry revealed robust near-field responses of the auditory periphery. Pre-operative pure-tone audiometric thresholds along with aided thresholds using the right cochlear implant are shown in Fig. 3. The patient’s young age limits quantifiable outcome data at this time, though the patient produces all six Ling sounds, demonstrates auditory-only receptive language ability by responding appropriately to questions, and has a steadily
Fig. 2. MRI and CT imaging of the brain and temporal bone. (A) T2-weighted axial MRI and (B) T1-weighted post-gadolinium fat-suppressed coronal MRI showing hypoplasia of the right cerebellum. The vermis is almost fused with the left cerebellum and is separated by a cleft that ends in the right side of the fourth ventricle. There was no hydrocephalus seen and the right pontomedullary junction and eighth cranial nerve root entry zone was normal. No large vestibular aquedect was seen on the axial T2weighted MR images. (C) Axial CT showing asymmetry of the right occipital skull and normal cochleae.
L. Kaufmann et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 93–96
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Table 2a Summary of children with WS and cochlear implants. (SCC = semicircular canal, HSC = horizontal semicircular canal, PSC = posterior semicircular canal). Study
No. of patients
Type of study
WS subtype
Inner ear malformation?
Mean age at CI (years)
Sugii et al. [12] Moon et al. [13]
1 1
Case report Case report
Type 2 Type 2
Almost normal cochlea Modiolar defect, hypoplasia of the lateral semicircular canal
4.0 Not mentioned
Migirov et al. [14]
5
Retrospective
4-Type 1 1-Type 2
None
4.8
Daneshi et al. [15]
6
Retrospective
4-Type 1 1-Type 2 1-Type 3
None
6.5
Loundon et al. [16] Pau et al. [17] Cullen et al. [6]
1 20 7
Retrospective Prospective Retrospective
Not mentioned Not mentioned Not mentioned
2.0 Not mentioned 3.1
This study
1
Case report
Type 2
Hypoplastic SCC, dysplastic vestibule Not mentioned 1-Enlarged endolymphatic sac 1-bilateral HSC dysplasia, bilateral PSC aplasia (only 5/7 had imaging) None
improving vocabulary. The 2-year-old well-child examination by his pediatrician noted normal neurological development, including age-appropriate gait, balance, and strength. Speech-language therapy has been provided by the local Early Intervention program. In order to achieve the increased benefits of binaural hearing, he underwent sequential bilateral cochlear implantation at age 29 months. Again intraoperative near-field responses were present and robust indicating appropriate stimulation of distal CN VIII. Behavioral testing confirms auditory perception with the second implant. 3. Discussion This report is the first description of isolated cerebellar hypoplasia in an infant with WS. Other abnormalities of the CNS are rare in WS and include anophthalmia, absent optic nerves, and Dandy–Walker malformation [7,8]. Congenital cerebellar deformities are seen in Dandy–Walker malformation, Joubert syndrome, and pontocerebellar hypoplasia [9]. Dandy–Walker malformation is the most common cause of a congenitally malformed cerebellum and is associated with a hypoplastic cerebellar vermis, an enlarged fourth ventricle and enlarged posterior skull [9]. Hypoplasia of the right cerebellar hemisphere is seen in our patient but his fourth ventricle was normal and ipsilateral occiput skull was small, conforming to the
1.5
reduced volume of the cerebellum. Joubert syndrome is characterized by congenital ataxia, hypotonia, episodic breathing dysregulation, mental retardation and malformation of the cerebellum and brainstem [9]. Our patient was otherwise healthy, developmentally appropriate and did not have pontocerebellar hypoplasia as his pons was normal on MR imaging. To the best of our knowledge there is only one case report of a 2year-old child with type 4 WS and cerebellar dysplasia in the setting of a Dandy–Walker malformation [7]. This patient presented with a small underdeveloped anterior cerebellar vermis, bilateral atrophic cerebelli and these changes were due to hydrocephalus [7]. This was an autopsy report and no cochlear implant was performed. Our patient does not have hydrocephalus. Other rare CNS findings have been described in WS patients. A myelomeningocele and neural crest anomalies in WS are usually associated with PAX3 mutations (seen in WS type 3) [10,11]. Another report describes a 3-year-old male patient with WS, hypothalamic hamartoma and anophthalmia. The optic nerves, optic chiasm, and optic tracts were absent [8]. A review of the English language literature, including this report, reveals only 8 papers that describe cochlear implant outcomes in WS (Tables 2a and 2b). A total of 42 WS patients were found in our review [6,12–17]. There is no mention of CNS abnormalities in these WS patients who underwent cochlear implantation. Outcomes were evaluated retrospectively in seven studies (22/42) [6,12–16] and
Table 2b Cochlear implant outcomes in children with WS (ESP = early speech perception test, PBK = phonetically based kindergarten test, EABR = electrically evoked auditory brainstem responses). Study
Device
Complications
Follow-up period (years)
Performance outcomes
Sugii et al. [12]
Cochlear Corp. mini 22
Not mentioned
2
Moon et al. [13]
Cochlear Corp. N24
Not mentioned
Migirov et al. [14]
Cochlear Corp. N22/24
Severe but controlled cerebrospinal fluid gusher 1-Device failure
I, III, and V waves on intraop EABRs, 58% open set word perception 30 dB threshold tone perception
4.4
Daneshi et al. [15]
Cochlear Corp. N22/24, Med El Combi 40+
Not mentioned
6.5
Loundon et al. [16] Pau et al. [17]
Cochlear Corp. N24 Not mentioned
None Not mentioned
3 1+
Cullen et al. [6]
Advanced Bionics Corp. Clarion, Cochlear Corp. N22/24, Med EI Combi 40+ Cochlear Corp. Freedom
1-Wound seroma 1-device failure
Not mentioned
None
0.5
This study
All patients had improved speech perception, average score of 81% in recognition of 2-syllable words Speech perception and intelligibility improved and it was possible to transfer all patients into regular educational settings 90% open set word perception 16/20 normal EABR intraop (10/16 with normal EABR had good open set speech perception 1 year postop, 6 lost to follow-up) 3/4 with abnormal EABR had detection of speech sounds at 1 year postop, 1 lost to follow-up 6/7 tested, all obtained some degree of closed- and open set speech perception, ESP 79–100%, PBK 40–80% Open set speech perception produces all six Ling sounds
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prospectively in one study (20/42) [17]. The subtype of WS was mentioned in 14 of these patients [12–15]. The most common subtype was type 1 WS (57% or 8/14), followed by type 2 (36% or 5/ 14) and type 3 WS (7% or 1/14) [12–15]. Radiologic data was provided in 21/42 of these WS patients with CIs and inner ear malformations were found in 19% (4/21) [6,12–16]. Hypoplasia or aplasia of the semicircular canals (SCC) was seen in 3/4 of WS patients with temporal bone anomalies [6,13,16]. Other findings included a large endolymphatic sac, dysplastic vestibule and a modiolar defect. The mean age at cochlear implantation was 3.6 years. Good performance outcomes were seen as the majority of the patients receive some level of speech perception. These psychophysical measures are supported by electrophysiologic confirmation of functional peripheral and central auditory pathways in the majority of WS patients [17]. Pau et al. found that intraoperative electrical auditory brainstem response testing (EABR) was a positive predictor for clinical outcomes following cochlear implant surgery in WS patients [17]. In his study 80% of the children with WS had normal EABRs, suggesting that the auditory pathways from the periphery to the auditory brainstem and midbrain are intact and functional in WS. Finally, we were unable to find any studies in the English literature that described implant outcomes in non-WS children with cerebellar abnormalities. 4. Conclusion This is the first study to describe a child with isolated cerebellar dysplasia in the setting of WS. Our patient underwent successful bilateral sequential cochlear implantation. To evaluate the outcomes of cochlear implantation in WS patients we reviewed 8 studies for a total number of 42 patients [6,12–17]. The majority of these patients was either type 1 or type 2 and most received some level of speech perception. Therefore, cochlear implantation remains a reasonable habilitative option in WS patients with congenital deafness, and CNS malformations are not an absolute contraindication for cochlear implantation in these patients. Temporal bone CT imaging in pediatric patients that demonstrate a skull abnormality as seen in our patient should be further evaluated with a high resolution MRI scan to exclude a CNS abnormality.
References [1] R.L. Touraine, T. Attie´-Bitach, E. Manceau, E. Korsch, P. Sarda, V. Pingault, et al., Neurological phenotype in Waardenburg syndrome type 4 correlates with Novel SOX10 truncating mutations and expression in developing brain, Am. J. Hum. Genet. 66 (2000) 1496–1503. [2] P.J. Waardenburg, A new syndrome combining developmental anomalies of eyelids, eyebrows and nose root with pigmentary defects of iris and head hair and congenital deafness, Am. J. Hum. Genet. 3 (1951) 195–253. [3] W.E. Nance, The genetics of deafness, Ment. Retard. Dev. Disabil. Res. Rev. 9 (2003) 109–119. [4] C.S. Nayak, G. Isaacson, Worldwide distribution of Waardenburg syndrome, Ann. Otol. Rhinol. Laryngol. 112 (2003) 817–820. [5] Y. Sznajer, C. Colde´a, F. Meire, I. Delpierre, T. Sekhara, R.L. Touraine, A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without hirschsprung disease, Am. J. Hum. Genet. 146A (2008) 1038–1041. [6] R.D. Cullen, C. Zdanski, P. Roush, C. Brown, H. Teagle, H.C. Pillsbury, et al., Cochlear implants in Waardenburg syndrome, Laryngoscope 116 (2006) 1273–1275. [7] B.J. Yoder, R.A. Prayson, Shah–Waardenburg syndrome and Dandy–Walker malformation: an autopsy report, Clin. Neuropathol. 21 (5) (2002) 236–240. [8] R.N. Sener, Cranial MR imaging findings in Waardenburg syndrome: anophthalmia and hypothalamic hamartoma, Comput. Med. Imaging Graph. 22 (1998) 409– 411. [9] K.J. Millen, J.G. Gleeson, Cerebellar development and disease, Curr. Opin. Neurobiol. 18 (1) (2008) 12–19. [10] J.S. Nye, D.G. McLone, J. Charrow, E.A. Hayes, Neural crest anomaly syndromes in children with Spina Bifida, Teratology 60 (1999) 179–189. [11] J.S. Nye, N. Balkin, H. Lucas, P.A. Knepper, D.G. McLone, J. Charrow, Myelomeningocele and Waardenburg syndrome (type 3) in patients with interstitial deletions of 2q35 and the PAX3 gene: possible digenic inheritance of a neural tube defect, Am. J. Hum. Genet. 75 (1998) 401–408. [12] A. Sugii, T. Iwaki, K. Doi, Y. Takahashi, K. Yamamoto, Y. Fuse, et al., Cochlear implant in a young child with Waardenburg syndrome, Adv. Otorhinolaryngol. 57 (2000) 215–219. [13] S.-K. Moon, H.S. Choi, S.J. Lee, Y.-H. Choung, K. Park, Cochlear implantation in a case with Waardenburg syndrome, Cochlear Implants Int. 1 (2004) 212–214. [14] L. Migirov, Y. Henkin, M. Hildesheimer, C. Muchnik, J. Kronenberg, Cochlear implantation in Waardenburg’s syndrome, Acta Otolaryngol. 125 (2005) 713– 717. [15] A. Daneshi, S. Hassanzadeh, M. Farhadi, Cochlear implantation in children with Waardenburg syndrome, J. Laryngol. Otol. 119 (2005) 719–723. [16] N. Loundon, I. Rouillon, N. Munier, S. Marlin, G. Roger, E.N. Garabedian, Cochlear implantation in children with internal ear malformations, Otol. Neurotol. 26 (2005) 668–673. [17] H. Pau, W.P.R. Gibson, K. Gardner-Berry, H. Sanli, Cochlear implantation in children with Waardenburg syndrome: an electrophysiological and psychophysical review, Cochlear Implants Int. 7 (2006) 202–206. [18] N. Bondurand, F.D. Moal, L. Stanchina, N. Collot, V. Baral, S. Marlin, et al., Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4, Am. J. Hum. Genet. 81 (2007) 1169–1185.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Dysplasia of the cerebellum in Waardenburg syndrome: Outcomes following cochlear implantation Lisa Kaufmann a, Todd B. Sauter b,c, Daniel J. Lee d,* a
Charite´ – Universita¨tsmedizin Berlin, Germany Department of Audiology, University of Massachusetts Medical School, Worcester, MA, USA c Department of Otolaryngology, University of Massachusetts Medical School, Worcester, MA, USA d Department of Otology and Laryngology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 July 2009 Received in revised form 7 October 2009 Accepted 8 October 2009 Available online 18 November 2009
This study provides the first description of isolated cerebellar dysplasia associated with Waardenburg syndrome (WS) and includes a review of cochlear implant outcomes in 42 WS patients. A 1-year-old male infant presented with speech delay, iris heterochromia, profound hearing loss, and an asymmetric, underdeveloped right occipital skull on CT imaging. Brain MRI demonstrated a hypoplastic right cerebellum, no hydrocephalus, normal auditory nerves and brainstem. He underwent successful bilateral sequential cochlear implantation. Cochlear implants remain a reasonable habilitative option for WS patients with congenital deafness, including those with cerebellar abnormalities. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Waardenburg syndrome Cochlear implant Cerebellar dysplasia
1. Introduction Waardenburg syndrome (WS) is a rare congenital disorder seen in 1/50,000 live births [1] and was first described by Waardenburg in 1951 [2]. The syndrome is regarded as a neurocristopathy resulting from an abnormal migration of the neural crest-derived cells [1]. There is genetic heterogeneity in WS and mutations involving at least eight genetic loci have been identified that result in four clinical subtypes [3]. The mode of inheritance depends on the type of WS (Table 1). Common features of WS include a hyperplastic, broad, and high nasal root, hyperplasia of the medial portions of the eyebrows, iris heterochromia, congenital deafness or unilateral hearing loss, and circumscribed albinism of the frontal hair [2]. Type 3, or Klein–Waardenburg syndrome, also presents with hypoplastic muscles and contractures of the upper limbs [4]. Type 4 (also known as Shah–Waardenburg syndrome) includes Hirschsprung’s disease and some of these patients have mental retardation [5]. Dystopia canthorum (telecanthus) is only seen in types 1 and 3 [4]. The sensorineural hearing loss seen in WS has been associated with a defect of the intermediate layer of the stria vascularis in the cochlea as a consequence of abnormal neural crest cell migration [3]. Hearing loss is found in about 20–55% of WS patients and this
* Corresponding author. Tel.: +1 617 573 3130; fax: +1 617 573 3914. E-mail addresses: [email protected], [email protected] (D.J. Lee). 0165-5876/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2009.10.007
syndrome accounts for about 2% of children with congenital deafness [6]. Structural abnormalities of the CNS are rare in WS and isolated dysplasia of the cerebellum in WS has not been previously reported. 2. Case presentation Our patient is a 1-year-old otherwise healthy male infant, the child of recent African immigrants, who presented to our office for a second opinion because of a concern of speech delay. The infant was the product of a fullterm pregnancy and uncomplicated delivery, but failed his first newborn hearing screening. An outside birth center re-screen using automated auditory brainstem response (AABR) apparently yielded a pass result for both ears. The parents denied a history of ear infections or trauma and the child had not been treated with any ototoxic medication. There was no history of gastrointestinal distress and he was thriving without difficulty. The exam was notable for brilliant sapphire eyes with iris heterochromia (Fig. 1). The child was healthy appearing, had normal facies, an unremarkable head and neck examination, and no other pigmentary abnormalities. Vestibular function and intelligence could not be assessed subjectively because the patient was not yet ambulatory and of very young age. Pure-tone thresholds were assessed using visual reinforcement audiometry techniques via ER-3A insert earphones (unaided) and in the sound field (aided) and revealed a severe to profound sensorineural
94
L. Kaufmann et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 93–96
Table 1 Subtypes of Waardenburg syndrome [4,5,6,18]. Waardenburg syndrome
Type 1
Type 2
Type 3 (Klein–WS)
Type 4 (Shah–WS)
Inheritance Gene
Autosomal dominant PAX3
Autosomal dominant/digenic MITF
Autosomal dominant PAX3
Autosomal dominant/recessive SOX10
Hearing loss Dystopia canthorum Other craniofacial abnormalities Pigmentary abnormalities Musculoskeletal abnormalities Hirschsprung´s disease Mental retardation
Yes Yes Yes Yes No No No
Yes No Yes Yes No No No
Yes Yes Yes Yes Yes No No
Yes No Yes Yes No Yes Yes
Fig. 1. Iris heterochromia. Upper panel: isohypochromia of the right iris and partial (or sectoral) heterochromia of the left eye in this child of African descent. He had a normal interpupillary distance and no dystopia canthorum (telecanthus).
hearing loss that was confirmed by comprehensive ABR testing at our facility. Tympanometry was normal bilaterally and distortion product otoacoustic emissions were absent. A radiologic evaluation included temporal bone computed tomography (CT) that demonstrated normal bony cochlear and vestibular development and an asymmetric occipital skull (Fig. 2C). Magnetic resonance imaging (MRI) of the head showed dysplasia of the cerebellum (Fig. 2A and B). Specifically, the caudal aspect of the right cerebellar hemisphere was smaller compared with the left side. The vermis appeared to be fused with the left cerebellum and was separated from the right side by a cleft that ended in the fourth ventricle. The fourth ventricle was otherwise normal in size and hydrocephalus was not seen. The brainstem was shifted slightly to the right side but the auditory nerve, root entry zone and cochlear nucleus region were grossly normal. The parents refused genetic testing. Our patient has two siblings, age 7 and 11, who are in good health with no history of hearing loss or other signs of a genetic syndrome. There was no family history of hearing loss except for one aunt with hearing loss that was felt to be secondary to measles. A diagnosis of WS type 2 was given to this child.
Fig. 3. Audiogram demonstrating pre-operative bilateral profound hearing loss, as well as aided thresholds in the borderline normal range when using right cochlear implant (CR).
The patient underwent uneventful cochlear implantation of the right ear with a Nucleus Freedom device (Cochlear Corporation) at age 17 months. The surgical anatomy was normal. A full insertion was achieved using the off-stylet technique. Intraoperative neural response telemetry revealed robust near-field responses of the auditory periphery. Pre-operative pure-tone audiometric thresholds along with aided thresholds using the right cochlear implant are shown in Fig. 3. The patient’s young age limits quantifiable outcome data at this time, though the patient produces all six Ling sounds, demonstrates auditory-only receptive language ability by responding appropriately to questions, and has a steadily
Fig. 2. MRI and CT imaging of the brain and temporal bone. (A) T2-weighted axial MRI and (B) T1-weighted post-gadolinium fat-suppressed coronal MRI showing hypoplasia of the right cerebellum. The vermis is almost fused with the left cerebellum and is separated by a cleft that ends in the right side of the fourth ventricle. There was no hydrocephalus seen and the right pontomedullary junction and eighth cranial nerve root entry zone was normal. No large vestibular aquedect was seen on the axial T2weighted MR images. (C) Axial CT showing asymmetry of the right occipital skull and normal cochleae.
L. Kaufmann et al. / International Journal of Pediatric Otorhinolaryngology 74 (2010) 93–96
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Table 2a Summary of children with WS and cochlear implants. (SCC = semicircular canal, HSC = horizontal semicircular canal, PSC = posterior semicircular canal). Study
No. of patients
Type of study
WS subtype
Inner ear malformation?
Mean age at CI (years)
Sugii et al. [12] Moon et al. [13]
1 1
Case report Case report
Type 2 Type 2
Almost normal cochlea Modiolar defect, hypoplasia of the lateral semicircular canal
4.0 Not mentioned
Migirov et al. [14]
5
Retrospective
4-Type 1 1-Type 2
None
4.8
Daneshi et al. [15]
6
Retrospective
4-Type 1 1-Type 2 1-Type 3
None
6.5
Loundon et al. [16] Pau et al. [17] Cullen et al. [6]
1 20 7
Retrospective Prospective Retrospective
Not mentioned Not mentioned Not mentioned
2.0 Not mentioned 3.1
This study
1
Case report
Type 2
Hypoplastic SCC, dysplastic vestibule Not mentioned 1-Enlarged endolymphatic sac 1-bilateral HSC dysplasia, bilateral PSC aplasia (only 5/7 had imaging) None
improving vocabulary. The 2-year-old well-child examination by his pediatrician noted normal neurological development, including age-appropriate gait, balance, and strength. Speech-language therapy has been provided by the local Early Intervention program. In order to achieve the increased benefits of binaural hearing, he underwent sequential bilateral cochlear implantation at age 29 months. Again intraoperative near-field responses were present and robust indicating appropriate stimulation of distal CN VIII. Behavioral testing confirms auditory perception with the second implant. 3. Discussion This report is the first description of isolated cerebellar hypoplasia in an infant with WS. Other abnormalities of the CNS are rare in WS and include anophthalmia, absent optic nerves, and Dandy–Walker malformation [7,8]. Congenital cerebellar deformities are seen in Dandy–Walker malformation, Joubert syndrome, and pontocerebellar hypoplasia [9]. Dandy–Walker malformation is the most common cause of a congenitally malformed cerebellum and is associated with a hypoplastic cerebellar vermis, an enlarged fourth ventricle and enlarged posterior skull [9]. Hypoplasia of the right cerebellar hemisphere is seen in our patient but his fourth ventricle was normal and ipsilateral occiput skull was small, conforming to the
1.5
reduced volume of the cerebellum. Joubert syndrome is characterized by congenital ataxia, hypotonia, episodic breathing dysregulation, mental retardation and malformation of the cerebellum and brainstem [9]. Our patient was otherwise healthy, developmentally appropriate and did not have pontocerebellar hypoplasia as his pons was normal on MR imaging. To the best of our knowledge there is only one case report of a 2year-old child with type 4 WS and cerebellar dysplasia in the setting of a Dandy–Walker malformation [7]. This patient presented with a small underdeveloped anterior cerebellar vermis, bilateral atrophic cerebelli and these changes were due to hydrocephalus [7]. This was an autopsy report and no cochlear implant was performed. Our patient does not have hydrocephalus. Other rare CNS findings have been described in WS patients. A myelomeningocele and neural crest anomalies in WS are usually associated with PAX3 mutations (seen in WS type 3) [10,11]. Another report describes a 3-year-old male patient with WS, hypothalamic hamartoma and anophthalmia. The optic nerves, optic chiasm, and optic tracts were absent [8]. A review of the English language literature, including this report, reveals only 8 papers that describe cochlear implant outcomes in WS (Tables 2a and 2b). A total of 42 WS patients were found in our review [6,12–17]. There is no mention of CNS abnormalities in these WS patients who underwent cochlear implantation. Outcomes were evaluated retrospectively in seven studies (22/42) [6,12–16] and
Table 2b Cochlear implant outcomes in children with WS (ESP = early speech perception test, PBK = phonetically based kindergarten test, EABR = electrically evoked auditory brainstem responses). Study
Device
Complications
Follow-up period (years)
Performance outcomes
Sugii et al. [12]
Cochlear Corp. mini 22
Not mentioned
2
Moon et al. [13]
Cochlear Corp. N24
Not mentioned
Migirov et al. [14]
Cochlear Corp. N22/24
Severe but controlled cerebrospinal fluid gusher 1-Device failure
I, III, and V waves on intraop EABRs, 58% open set word perception 30 dB threshold tone perception
4.4
Daneshi et al. [15]
Cochlear Corp. N22/24, Med El Combi 40+
Not mentioned
6.5
Loundon et al. [16] Pau et al. [17]
Cochlear Corp. N24 Not mentioned
None Not mentioned
3 1+
Cullen et al. [6]
Advanced Bionics Corp. Clarion, Cochlear Corp. N22/24, Med EI Combi 40+ Cochlear Corp. Freedom
1-Wound seroma 1-device failure
Not mentioned
None
0.5
This study
All patients had improved speech perception, average score of 81% in recognition of 2-syllable words Speech perception and intelligibility improved and it was possible to transfer all patients into regular educational settings 90% open set word perception 16/20 normal EABR intraop (10/16 with normal EABR had good open set speech perception 1 year postop, 6 lost to follow-up) 3/4 with abnormal EABR had detection of speech sounds at 1 year postop, 1 lost to follow-up 6/7 tested, all obtained some degree of closed- and open set speech perception, ESP 79–100%, PBK 40–80% Open set speech perception produces all six Ling sounds
96
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prospectively in one study (20/42) [17]. The subtype of WS was mentioned in 14 of these patients [12–15]. The most common subtype was type 1 WS (57% or 8/14), followed by type 2 (36% or 5/ 14) and type 3 WS (7% or 1/14) [12–15]. Radiologic data was provided in 21/42 of these WS patients with CIs and inner ear malformations were found in 19% (4/21) [6,12–16]. Hypoplasia or aplasia of the semicircular canals (SCC) was seen in 3/4 of WS patients with temporal bone anomalies [6,13,16]. Other findings included a large endolymphatic sac, dysplastic vestibule and a modiolar defect. The mean age at cochlear implantation was 3.6 years. Good performance outcomes were seen as the majority of the patients receive some level of speech perception. These psychophysical measures are supported by electrophysiologic confirmation of functional peripheral and central auditory pathways in the majority of WS patients [17]. Pau et al. found that intraoperative electrical auditory brainstem response testing (EABR) was a positive predictor for clinical outcomes following cochlear implant surgery in WS patients [17]. In his study 80% of the children with WS had normal EABRs, suggesting that the auditory pathways from the periphery to the auditory brainstem and midbrain are intact and functional in WS. Finally, we were unable to find any studies in the English literature that described implant outcomes in non-WS children with cerebellar abnormalities. 4. Conclusion This is the first study to describe a child with isolated cerebellar dysplasia in the setting of WS. Our patient underwent successful bilateral sequential cochlear implantation. To evaluate the outcomes of cochlear implantation in WS patients we reviewed 8 studies for a total number of 42 patients [6,12–17]. The majority of these patients was either type 1 or type 2 and most received some level of speech perception. Therefore, cochlear implantation remains a reasonable habilitative option in WS patients with congenital deafness, and CNS malformations are not an absolute contraindication for cochlear implantation in these patients. Temporal bone CT imaging in pediatric patients that demonstrate a skull abnormality as seen in our patient should be further evaluated with a high resolution MRI scan to exclude a CNS abnormality.
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