https://orcid.org/0000-0001-5177-1460
Abstract
Waardenburg syndrome is a rare genetic disorder characterized by hearing loss in association with pigmentary defects of the skin, hair and eyes. It is caused by the gene mutation involved in the development of melanocyte. A five years old, female child attended our hospital because of bilateral profound sensorineural hearing loss detected at 4 months of age. She had blue eyes, dystopia canthorum, white forelock of hair, leukoderma on the forehead and nose, broad nasal root. She was diagnosed with Waardenburg syndrome type I. Congenital hearing loss was managed by cochlear implant surgery. The audiological result was normal with activation of implant post-operatively. Her CAP score was 7 at four years after surgery. Although Waardenburg syndrome is a rare disorder, it could affects significantly to patient’s development, especially congenital sensorineural hearing loss.
Introduction
Waardenburg syndrome (WS) is a genetic disorder that can cause hearing loss and changes in coloring of the hair, skin and eyes. This syndrome was first described by the Dutch Ophthalmologist Petrus Johannes Waardenburg in 1951 [Citation1]. It affects 1 in 40000 births and accounts for 2–5% of all cases of congenital hearing loss. Males and females were affected relatively equally. In most cases, WS is inherited as autosomal dominant manner. However, some cases appear to have an autosomal recessive pattern of inheritance [Citation2,Citation3].
There are four types of WS which are distinguished by their clinical presentations and genetic cause. Type I and II have very similar features, except for the sign of dystopia canthorum is common in type I, while type II does not. Type III (known as Klein – Waardenburg syndrome) includes anomaly of the arms and hands associated with hearing loss and changes in pigmentation. Type IV (sometimes called Waardenburg – Shah syndrome or Waardenburg – Hirschsprung disease) has signs and symptoms of not only WS but also Hirschsprung disease.
These genes are involved in the formation and development of pigment-producing cells known as melanocytes. They make a pigment called melanin, which contributes to skin, hair, eyes color and plays an important role in the normal function of the inner ear. Mutations in any of these genes can disrupt the normal development of melanocytes, leading to abnormal pigmentation of the skin, hair and eyes, as well as hearing loss on examination.
Sensorineural hearing loss, especially bilateral hearing loss, is a common clinical feature in WS, with a prevalence of 71%. It is due to abnormalities or absence of the organ of Corti [Citation4]. The diagnosis of WS is established in patient with two major criteria or one major plus two minor criteria, according to Waardenburg Consortium [Citation5].
Case presentation
A 5-year-old female patient came to ENT Hospital of Ho Chi Minh City (Vietnam) for examination because of hearing loss was detected at 4 months of age. Examination showed the turquoise blue iris of both eyes, the sideways displacement of the inner angles of the eyes (partially covering the medial part of the sclera on both sides), the white hair on the forehead, the vitiligo occurred on the skin of the forehead and nose, the broad nasal root. In addition, we did not notice any abnormalities on endoscopy.
About medical history, there were not any anomalies noted during pregnancy related to risk factors for congenital hearing loss (such as TORCH infections, etc). However, we noted that her grandmother and brother also had a change in the iris color, but there were no loss of hearing recorded. Audiological results showed that this baby had bilateral profound hearing loss (Figure ).
Figure 1. Pre-operative audiogram of the patient showed the bilateral profound hearing loss with Pure Tone Average (PTA) > 90 dB.
We conluded that it was most likely a case of WS. Therefore, we advised her to screen for other congenital anomalies, especially the eyes, musculoskeletal and gastrointestinal examination. Fortunately, all results were normal. Additionally, the baby was also performed genetic testing for hearing loss (including 277 genes) and the result recorded that she had a mutation of the PAX3 gene (paired box gene 3) (Table ).
Table 1. The genetic test result: the mutation of the PAX gene.
The patient was diagnosed as WS type I. She had been treated with hearing aid for 3 months but did not respond. And then, she received a cochlear implant surgery at our hospital (the right ear at 15 months old and the left ear at 4 years old). We did not recognize any complications or ear anomalies during surgery. The baby was trained with a language program designed particularly by speech therapist after surgery.
The hearing and speech rehabilitation were assessed by using audiometry and CAP score. For the right ear, PTA (frequency average of thresholds at 500, 1000, 2000 and 4000 Hz) collected at four years after implantation was 11.25 dB. For the remaining ear at one year after surgery, PTA was 15 dB. In addition, she achieved CAP of 7 after four years of surgery (she can use the telephone with a familiar talker). This was a positive results after cochlear implant surgery (Figure ).
Figure 2. Post-operative audiogram of the patient (A: right ear; B: left ear). The results were better than the normal ‘speech banana’ (red dots), indicated that the ability to hear and understand speech improved remarkably.
Discussion
WS1 is a rare dominant autosomal disorder characterized by congenital sensorineural hearing loss in association with pigmentary defects of the skin, hair and eyes. The prevalence of hearing loss in WS1 is estimated to be approximately 60%, the most common type is bilateral profound hearing loss. The clinical manifestations are variable even within a family. The diagnosis of WS is established in patient with two major criteria or one major plus two minor criteria, according to Waardenburg Consortium.
Apart from the aforementioned symptoms, the sign of dystopia canthorum is considered to be the most important symptoms to distinguish WS1 from WS2 (apart from differences in mutant genes, WS1 and WS2 have similar clinical manifestations, except for the different types of gene mutations and this sign). Genes related to four type of WS is illustrated in Table . The prevalence of temporal bone abnormalities may be up to 50%, the most commonly inner ear malformations are enlarged vestibular aqueducts and semicircular canal anomalies [Citation6]. The surgeon should be well aware of these abnormalities when doing cochlear implant surgery.
Table 2. Genes related to WS.
Treatment of WS1 includes cochlear implant surgery to deal with hearing loss and screening for family members who have hearing loss. In addition, maternal folic acid supplementation in pregnancy has been recommended to minimize the risk of having a child associated with brain and spinal cord abnormalities [Citation7]. Moreover, skin pigmentation abnormalities are also associated with an increased risk of skin cancer, so patients are also recommended avoiding direct sunlight exposure (wearing a jacket, hats, sunglasses …) [Citation2,Citation3].
The patient in our study was a typical case of WS1 with four major and two minor standards according to the Waardenburg Consortium. Furthermore, the results of PAX3 mutation also increased the diagnostic accuracy of WS1. It is reported that the PAX3 mutations presented in more than 90% of patients with WS1. This high frequency of PAX3 mutation in WS1 suggests that clinical diagnosis of WS1 could be facilitated by PAX3 genetic analysis [Citation8]. Hence, genetic testing in the diagnosis of WS is very important, especially for those with suspected WS. However, currently in Vietnam, not all patients can afford to pay for a genetic test. Therefore, it is important to think about this syndrome based on the suggested clinical presentations in order to determine early diagnosis and treatment. In fact, apart from diagnosing patient with WS1, we also advised her parents to screen some congenital defects for her brother. Fortunately, he did not have any abnormalities except for the change in his iris color.
Several researchers reported that children implanted before age 2 years had significant speech perception and language development over those after 2 years of age [Citation9]. Dunn et al. showed that the bilateral cochlear implantation group had significantly better performance on speech perception in noise compared to the unilateral implantation [Citation10]. Moreover, the sound localization was significantly better when tested in the bilateral cochlear implantation group [Citation11]. These results supported the hypothesis that bilateral cochlear implantation is more beneficial than unilateral implantation. However, because of expensice prize, the patient received her first cochlear implant in the right ear at 15 months old and the second implant in the left ear after 3 years.
The post-operative audiological data was improved significantly (normal hearing with activation of implant post-operatively compared to profound hearing loss pre-operatively). Currently, she could talk with her family members through the phone and live like a normal child, equivalent to CAP of 7 (the highest level of this score). This reflected a good outcome, probably because of early cochlear implantation.
Conclusion
Although Waardenburg syndrome is a rare disorder, it could affects significantly to patient’s development, especially congenital sensorineural hearing loss. Early recognizing of this syndrome and screening of other associated abnormalities will aid doctors in making management strategy to obtain an optimal outcome.
Consent information
Written informed consent was obtained from guardians of the patient to publish this case report. Any personal details and diagnostic images were anonymized to meet the confidentiality requirements. Institutional approval was not required to publish the case details.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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