Audiological and vestibular findings in the Kabuki syndrome^†

INTRODUCTION

Kabuki syndrome (KS, Kabuki make-up syndrome, Niikawa–Kuroki syndrome) was firstly described in 1981 by two groups of Japanese authors [Niikawa et al., 1981; Kuroki et al., 1981]. These authors suggested that the core of the phenotypic spectrum of KS is rather narrow and clearly defined [Niikawa et al., 1988] and most of the patients have the following five cardinal manifestations: (1) a distinctive face (100%) that resembles the make-up worn by Japanese actors in Kabuki theatre, characterized by long palpebral fissures, eversion of the lateral third of the lower eyelids, arched eyebrows with the lateral one-third dispersed, a depressed nasal tip and prominent ears [Matsumoto and Niikawa, 2003]; (2) skeletal anomalies (92%), including brachydactyly V and a deformed spinal column, with or without sagittal cleft vertebrae; (3) dermatoglyphic abnormalities (93%), including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; (4) mild to moderate mental retardation (92%); (5) postnatal growth deficiency (83%) [Matsumoto and Niikawa, 2003]. Major malformations of various organs have also been described.

Subsequently further reports have hypothesized different clinical criteria to diagnose the KS [Schrander-Stumpel et al., 1994; Digilio et al., 2001]; more recently Armstrong et al. 2005 outlined “…the diagnosis of KS is a clinical one for which no validated diagnostic criteria have been published.”

Since the first observations, approximately more than 350 cases have been reported from all over the world [Matsumoto and Niikawa, 2003] with a prevalence of 1/32,000 estimated in the Japanese population [Niikawa et al., 1988]. Even though the occurrence in monozygotic twins indicates a genetic base [Lynch et al., 1995], the etiology of KS is still unknown. Recent literature suggests an autosomal dominant inheritance with variable expressvity. The occurrence of a duplication 8p23.1p22 was described in six unrelated patients by Milunsky and Huang 2003 but several studies on a total of 122 KS subjects did not confirm this association. Very recently Maas et al. 2007 suggested that KS phenotype could be due to disruption of C20orf133 gene. In their article they studied the mouse embryo expression of the gene itself finding a good correlation with the medical problems related to the syndrome; an expression of the gene in the cells lining the vestibulocochlear and coclear duct was evident as well.

This evidence can be possibly correlated at the clinical level with a high prevalence of otolaryngologic problems, such as ear diseases (92%), hearing loss (82%), and airways problems (58%) [Peterson-Falzone et al., 1997] in patients with KS.

Minor external ear anomalies are typical of this syndrome and have been described by most authors: prominent large and cup-shaped ears are the most common findings (85–100%) but preauricular fistula and microtia have also been reported along with other otolaryngologic malformations such as pretragal pits [Fong et al., 2001].

Hearing loss, mainly due to recurrent otitis media, is also a common finding in KS and it is reported with a frequency ranging from 24% to 82% and can be conductive, sensorineural or mixed. Chronic otitis media is extremely frequent (55–92%) in patients with KS during childhood (55% [Niikawa et al., 1988], 92% [Peterson-Falzone et al., 1997]). It is probably related either to cleft palate and abnormal development of the Eustachian tube or to immune deficiency [Niikawa et al., 1981]. Sensorineural hearing loss is very rare in KS and was reported in 2005 in two individuals with bilateral absence of the cochlea with dilated dysplastic vestibule and unilateral enlarged vestibule by Tekin et al. 2006. Other anatomic abnormalities such as Mondini dysplasia and ossicular malformations have also been reported [Say et al., 1993; Toutain et al., 1997]. Dysplasia of the cochlea associated with an enlarged vestibule has been described in four patients [Say et al., 1993; Igawa et al., 2000]. This low prevalence could also be due to incomplete neuro-radiological investigations reported up to now into medical literature.

Very few reports deal with the vestibular system in Kabuki patients. No functional investigation of the vestibular function has been made until now. The aim of the present report was to investigate the audiological and vestibular aspects in patients with KS in order to define the best clinical management.

MATERIALS AND METHODS

Ten patients affected by KS, seven males and three females, with age ranging from 10 to 25 years (mean age: 14.5 ± 5.1) were gathered in a collaborative study between the Audiology Unit and the Paediatric Department of the University of Milan (Fig. 1). The KS diagnosis had been previously carried out by the Generalist of the Pediatric Unit according to the above listed major criteria (postnatal short stature, skeletal anomalies, moderate mental retardation, dermatoglyphic anomalies and characteristic facial dysmorphism). Table I summarizes the clinical findings of each observed patient. All patients had standard karyotype, FISH study for 22q11.2 microdeletions and FMR1 gene molecular study and all showed normal results. All the subjects underwent a pediatric routine follow-up and were successively referred to the Audiology Unit for audiological and vestibular evaluation.

RESULTS

The results have been divided into audiological and vestibular ones (Table III). While all the patients completed the audiological evaluation, four patients could not perform the entire vestibular protocol for lack of cooperation and the already known ear pathology. All patients had a mental retardation (Table I). Patient cooperation was present in 7/10 and the mental capabilities only partially influenced the cooperation during the examinations.

DISCUSSION

In literature the prevalence of hearing loss in KS patients ranges widely from 24% up to 82% of the patients [Niikawa et al., 1988: 24%; 50%, Schrander-Stumpel et al., 1994: 50%, Burke and Jones, 1995: 50%; Peterson-Falzone et al., 1997: 82%; Matsumoto and Niikawa, 2003: 27%]. A review of the literature by Toutain et al. 1997 confirmed that hearing loss is a major component of KS with a frequency of about 32%.

In our study only three patients showed normal hearing. This prevalence of hearing loss appears relatively high compared to the majority of other authors, probably because of the classification chosen to define normal hearing and the different classes of hearing loss. We used Goodman's classification modified by Clark that considers normal hearing the average threshold of 0.5, 1, and 2 KHz below or equal to 15 dBHL because Clark points out that for young children, even a 20–25 dB threshold may indicate a significant decrease in sensitivity and classifies such thresholds as slight hearing losses. We found that a slight, mild or moderate hearing loss was extremely frequent since it was evident in the majority of the affected ears (10/13–76.9%).

In our group of 10 subjects, all hearing losses were conductive or mixed. Like other authors, we did not find any sensorineural hearing loss, and confirming that it is a rare disorder in Kabuki patients.

In the ears with hearing loss the most frequent finding was otitis media and its consequences (otitis media with effusion, serous adhesive otitis media, antroatticotomy and tympanomastoidectomy) observed in 7 of 13 (54%).

In KS patients, the frequency of otitis media is likely related both to the high incidence of infections and to Eustachian tube impairment. In our study, none of these seven patients affected by otitis media and its complications have had a cleft palate. These data support Peterson-Falzone et al. 1997 who indicated that the prevalence of ear disease in KS cannot be explained solely on cleft palate and suggested that hearing loss in KS requires the diagnosis and treatment expertise of audiologists and otolaryngologists.

The hearing loss in the other six of 13 hearing impaired ears was related to aural atresia in one ear and, in five cases, it was associated with a normal otomicroscopy and tympanometry with the absence of stapedial reflexes suggesting a possible ossicular fixation. As reported in literature [Peterson-Falzone et al., 1997], the skeletal anomalies frequently observed in KS might also involve the middle ear ossicles with a fixation of the joints [1978].

To our knowledge there is no report in literature concerning the investigation of the vestibular function in Kabuki patients.

As reported in other syndromes previously known mainly for external or middle ear anomalies, such as the CHARGE syndrome, abnormal vestibular functions have been recently seen to be relevant in the development of motor and balance disorders [Sanlaville and Verloes, 2007]. Such findings have led to a better delineation of the syndrome [Verloes, 2005]. Therefore it is not unreasonable to posit that KS could include vestibular anomalies that potentially could be screened clinically avoiding invasive diagnostic assessments (CT or MRI with sedation).

In our experience the vestibular evaluation was difficult in these subjects since they cannot offer the cooperation needed for caloric examination and VEMPs. The labyrinthic study with caloric test can be carried out exclusively in cooperative patients with no anomalies of the external ears, tympanic membrane perforation, or oto-surgical outcomes. In our patients caloric tests was possible in only six subjects (60%).

Evaluation of the vestibular system is challenging in KS because a nystagmus could be close to ocular or CNS pathology and the musculoskeletal anomalies mandate the study of postural stability.

In the restricted group of patients examined for the vestibular function, 92% showed normal results. In particular, all the ears studied with caloric tests were normoreflective. As the vestibular caloric stimulation was impossible in the patient with aural atresia, the implementation of boneVEMPs was useful, revealing a saccular impairment on the side of the abnormal ear. On the contrary, airVEMPs did not seem to be a valid tool to study the saccular function because of the high prevalence of airbone gap in KS hearing thresholds.

Static posturography performed in patients with KS did not show significant results either. The vestibular subsystems sensory analysis demonstrated a visual or somatosensory impairment that was easily related to the clinical history of the patient.

In view of these findings, it would be advisable to study each patient affected by KS through audiological examinations and reserve the vestibular assessment for selected patients with vestibular symptoms, with sensorineural hearing loss or inner ear abnormalities. In conclusion we recommend audiological evaluation in all patients with KS and vestibular assessment in selected individuals.