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Item Snoring loudly during sleep Irregular or stopped breathing (apnoea) during sleep Many visits to the family doctor or A&E department Many phone calls to the doctor or NHS Direct Taking antibiotics over and over for less than 2 weeks at a time Taking antibiotics for more than 2 weeks straight Frequent ear ache or ear infections Repeated short-term throat infections that last less than 2 weeks Constant, or chronic, throat infections that last more than 2 weeks Breathing through the mouth during the day Noisy breathing during the day Problems with poor appetite or poor eating habits (choking on food, etc.) Missing school days due to sore throats Daytime sleepiness

No Very mild Mild or slight Moderate Severe Problem as bad problem problem problem problem problem as it could be 0 0 0 0 0

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0 0 0

1 1 1

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Please enter any further important symptoms that occur as a result of your child’s throat problems that we have missed from the list above, and give each a rating from 0 to 5 like the ones already listed.

Waardenburg syndrome: more common than you think! Zaman, A., Capper, R. & Baddoo, W. Ear, Nose and Throat Department, Doncaster and Bassetlaw NHS Foundation Trust, Doncaster, UK Accepted for publication 3 September 2014

Dear Editor, Waardenburg syndrome is an autosomal dominant inherited genetic condition that can result in ocular, pigmentary and systemic abnormalities.1 Hence, patients can present with congenital sensorineural hearing loss, dystopia canthorum and pigmentary disturbances of the iris, hair and skin.2 Systemically, there can be skeletal muscle contractures and Hirschsprung’s disease.3 Four different types of Waardenburg syndrome have been described based on genotypic and phenotypic variations classified in accordance with the Waardenburg Syndrome Consortium Criteria for diagnosis.3,4 Waardenburg syndrome type 1 and type 2 are more common than type 3 and type 4.4 Diagnosis of the syndrome is clinical.3 The criteria used for diagnosis are listed in Table 1. They are divided into Correspondence: A. Zaman, Flat 112, The Whitehouse Apartment, 9, Belvedere Road, London SE1 8YP, UK. Tel.: +44863117046; Fax: 01302 647276; e-mail: [email protected]

major and minor criteria,4,5 and different combinations are used to diagnose the different subtypes of Waardenburg syndrome (Table 1). Waardenburg syndrome type 1 (WS1) is diagnosed when 2 major criteria or 1 major and 2 minor criteria are fulfilled.5



Table 1. Criteria used in diagnosis of Waardenburg Major criteria

Minor criteria

Congenital sensorineural Congenital hypopigmentation hearing loss of the skin Pigmentary disturbance of iris Synophrys (eyebrows which meet) Pigmentary disturbance of Broad high nasal root hair (white forelock) Dystopia canthorum Hypoplasia of alae nasi Affected first degree relative Premature greying of hair

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Waardenburg syndrome type 2 (WS2) can be diagnosed in individuals having 2 major criteria (excluding dystopia canthorum).5 Waardenburg syndrome type 3 (WS3), better known as Klein–Waardenburg, is diagnosed in patients who fulfil the same criteria as patients with type 1 but also have musculoskeletal abnormalities.4,5,8 Waardenburg syndrome type 4 (WS4), better known as Waardenburg–Shah, is diagnosed in patients who fulfil the same criteria as patients with type 1 but suffer from Hirschsprung disease concurrently.5 WS4 differs from the others in having an autosomal recessive inheritance. Current data on the incidence of Waardenburg syndrome vary worldwide, but the prevalence of the disease is estimated to be 1 in 42 0004 (or 0.024 per 1000). Waardenburg syndrome accounts for 2–5% of patients with congenital hearing loss.6

• •

Case series

We present seven cases of newly diagnosed Waardenburg syndrome (or suspected Waardenburg syndrome) in Doncaster and Bassetlaw Hospitals from 2003 to 2010. These cases were diagnosed following newborn hearing screening test where sensorineural hearing loss was identified. Of 33 732 patients who underwent newborn hearing screening, 7 patients with suspected Waardenburg syndrome were identified and referred on to a regional genetics unit. Diagnosis of Waardenburg syndrome was made based on the physical attributes in accordance with the Waardenburg Syndrome Consortium Criteria. Table 2 shows the diagnostic features of four infants with a confirmed diagnosis of Waardenburg syndrome, and the results of other aetiological investigations that were performed. Table 3 shows the same information for three infants in whom a diagnosis of Waardenburg syndrome is suspected. Discussion

Newborn hearing screening aims to identify congenital hearing loss at birth, so that appropriate management can be instigated early and investigations performed to attempt to identify the cause of deafness. Between July 2003 and December 2010, 33 732 neonates were screened at Doncaster & Bassetlaw Hospitals NHS Foundation Trust. A total of 76 children were found to have sensorineural hearing loss, ranging from mild to profound, affecting one ear or both, an incidence of 2.25 per 1000. Aetiological investigations are offered to all infants diagnosed with hearing loss. These include urinalysis, TORCH screening (toxoplasma, rubella, cyto© 2014 John Wiley & Sons Ltd  Clinical Otolaryngology 40, 41–64

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megalovirus and herpes simplex), electrocardiogram (ECG), family audiograms and other appropriate blood tests and genetic testing for mutations/deletions in connexion 26 and 30 proteins. Families are offered a referral to the regional genetic service. MRI scanning is not yet routinely performed, but infants who are referred for consideration for cochlear implantation are scanned at the implant centre. Of the 76 infants identified with sensorineural hearing loss, four were diagnosed with Waardenburg syndrome and three more are suspected to have the syndrome. Waardenburg syndrome is a relatively common genetic cause of sensorineural hearing loss and is estimated to be responsible for 2–5% of cases of congenital hearing loss.6 Some of the clinical features are well recognised, but other minor features are easily overlooked. Several gene mutations may result in Waardenburg syndrome. Typically, these genes are involved in the development of pigment-producing cells called melanocytes.7 Mutations in the PAX3 gene result in Waardenburg syndrome type 18 and type 3,7 whilst mutation in the MITF gene is responsible for type 2 Waardenburg syndrome.7,9 Mutations in the SOX10, EDN3 or EDNRB genes are responsible for Waardenburg syndrome type 4.7,10 Waardenburg syndrome type 1 and type 3

PAX3 genes code for PAX proteins. These direct the activity of other genes that signal neural crest cells to form specialised tissues and cell types such as limb muscles, craniofacial skeleton and melanocytes.1 Hence, a mutation in this gene results in abnormalities of pigmentation, craniofacial development and musculoskeletal development of the limbs, which manifests as Waardenburg syndrome. Waardenburg syndrome type 2

MITF gene mutation results in mutation in a transcription factor that controls the development and function of melanocytes. Waardenburg syndrome type 4

The SOX10 gene codes for the SOX10 protein. This protein directs the activity of other genes that signal neural crest cells and is essential for the formation of enteric nerves.7 Hence, a SOX10 gene defect manifests in Waardenburg Syndrome type 4. Mutations in the EDN3 and the EDNRB genes result in mutated proteins called endothelin 3 and endothelin receptors, respectively.7,10 These proteins are required in the proper functioning of the neural crest cells and also in the formation of the enteric nerves.

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Table 2. Patients diagnosed based on the Waardenburg Syndrome Consortium Criteria Patient

Major criteria

Minor criteria

Other

Investigations performed

Diagnosis

1

Congenital SNHL (right severe, left profound, non-progressive)

Broad high nasal root

Family history of heterochromia irides (maternal grandfather)

Urinalysis – blood negative TORCH screen – Rubella IgM negative, Toxoplasmosis IgM negative CMV IgG detected, IgM negative. Urine CMV PCR not detected ECG normal QT interval Maternal audiogram – very mild high-frequency hearing loss Referred to genetic service at 5 months

WS type 1 (made by geneticist)

Family history of premature greying*

Urinalysis – blood negative TORCH screen – Rubella IgM negative CMV IgG, IgM negative ECG – QT interval normal FBC normal TFTS normal MRI scan at implant centre Referred to genetic service at 8 months

WS type 2

No investigations performed.

WS type 2 (made by geneticist)

2

3

4

8-year follow-up Dystopia canthorum W index = 3.16 Congenital SNHL (bilateral profound, non-progressive)

3-year follow-up, moved out of area Heterochromia irides Congenital SNHL (right severe, left moderate, progressed to bilateral profound) 8-year follow-up Heterochromia irides. Hypopigmentation of skin W Index = 1.4697 – 1.6932 Congenital SNHL (bilateral profound, non-progressive) 6-year follow-up Heterochromia irides

MRI scan at implant centre Referred to genetic service at 7 months

Cleft palate

No investigations performed.

Possible affected first degree relative. (maternal profound hearing loss and premature greying*)

MRI scan at implant centre Referred to genetic service at 1 month

WS type 2 (made by geneticist)

*Premature greying defined as under the age of 20 years. SNHL, sensorineural hearing loss; TORCH, toxoplasma, rubella, cytomegalovirus and herpes; CMV, cytomegalovirus; ECG, electrocardiogram; FBC, full blood count; TFT, thyroid function test.

Genetic testing and counselling

Molecular genetic testing can be carried out to identify a gene mutation which may result in Waardenburg syndrome.8 In the United Kingdom currently, the UK Genetic Testing Network is able to carry out tests investigating

mutations in the PAX3 gene.11 Sequence analysis and deletion/duplication analysis can be carried out on the gene. In families with known PAX3 mutation, prenatal testing is a possibility. However, the test is not capable of predicting the clinical manifestation or the severity of disease in cases © 2014 John Wiley & Sons Ltd  Clinical Otolaryngology 40, 41–64

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Table 3. Patients suspected to have Waardenburg syndrome based on Waardenburg Syndrome Consortium Criteria Patient

Major criteria

5

Congenital SNHL (bilateral moderate, non-progressive)

Minor criteria

Other

Investigations performed

Diagnosis (probable)

Possible affected relative (dystopia canthorum + early greying*)

Urinalysis – no blood family audiograms – both parents normal TSH – normal Connexin 26 + 30 – no pathogenic mutation/ deletion Grandmother – dystopia canthorum (PAX 3 gene test in grandmother normal) Referred to genetic service at 16 months Urinalysis – no blood family audiograms – mother + sibling found to have SNHL TSH - normal Referred to genetic service at 30 months Urinalysis – no blood ECG – normal QT interval Connexin 26 + 30 – no pathogenic mutation/deletion Referred to genetic service at 39 months

WS type 1 (made by geneticist)

5-year follow-up 6

Congenital SNHL (bilateral mild, non-progressive)

Possible affected first degree relative (SNHL – bilateral mild and premature greying*)

7-year follow-up 7

Congenital SNHL (right severe, left moderate, non-progressive)

Possible affected first degree relative (white forelock and premature greying*)

6-year follow-up

WS type 2 (made by geneticist)

WS type 2 (made by geneticist)

*Premature greying defined as under the age of 20 years. SNHL, sensorineural hearing loss; ECG, electrocardiogram; TSH, thyroid stimulating hormone.

where the gene mutation has been inherited.8 Women at increased risk of having a child with Waardenburg syndrome are advised to take folic acid supplementation during pregnancy as there is increased risk of neural tube defects associated with this condition.8

with a hearing loss through the newborn hearing screening programme. Keypoints



Conclusion

Waardenburg syndrome has a reported prevalence of 1 in 42 0004 (0.024 per 1000). We have identified four new cases with another probable three cases born between 2003 and 2010 in two District General Hospitals with an annual delivery rate of around 4500–5000 per year. Using our newborn hearing screening database where over 33 000 neonates underwent screening, we obtained an incidence of 0.119–0.208 per 1000 for Waardenburg syndrome. We believe that the prevalence of Waardenburg syndrome is much higher than previously reported and that good clinical acumen can result in better diagnosis of the syndrome. In time, this will be complemented by better genetic testing. A positive diagnosis clearly has an impact on the family of a child identified © 2014 John Wiley & Sons Ltd  Clinical Otolaryngology 40, 41–64

• •

A diagnosis of Waardenburg Syndrome is made in accordance with the Waardenburg Syndrome Cnsortium Criteria for diagnosis. We believe that the prevalence of Waardenburg Syndrome is much higher than previously reported. Increased awareness and good clinical acumen can result in better diagnosis of the syndrome.

Conflicts of interest

None declared. Ethical consideration

No identifiable patient information included.

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References 1 Wang J., Li S., Xiao X. et al. (2010) PAX3 mutations and clinical characteristics in Chinese patients with Waardenburg syndrome type 1. Mol. Vis. 16, 1146–1153 2 Pingault V., Ente D., Dastot-Le M.F. et al. (2010) Review and update of mutations causing Waardenburg syndrome. Hum. Mutat. 31, 391–406 3 Charrow J. (2007) Different colored eyes. Waardenburg syndrome. Pediatr. Ann. 36, 277–278 4 Read A.P. & Newton V.E. (1997) Waardenburg syndrome. J. Med. Genet. 34, 656–665 5 Mehta M., Sethi S., Pushker N. et al. (2010) Delayed presentation of children with Waardenburg syndrome. J. Pediatr. Ophthalmol. Strabismus 47, 382–383 6 Nayak C.S. & Isaacson G. (2003) Worldwide distribution of Waardenburg syndrome. Ann. Otol. Rhinol. Laryngol. 112, 817–820 7 Genetics Home Reference – A service of the U.S. National Library of Medicine. Genetics of Waardenburg Syndrome [Online]. (2006)

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http://ghr.nlm.nih.gov/condition/waardenburg-syndrome [accessed on 9 January 2012] Milunsky J.M. (2009) Waardenburg syndrome type 1. In Gene Reviews, Pagon R.A., Bird T.D. & Dolan C.R. et al. (eds), University of Washington, Seattle. [Online] http://www.ncbi.nlm.nih.gov/ books/NBK1531 [accessed on 20 January 2012] Kiani R., Gangadharan S.K. & Miller H. (2007) Case report: association of waardenburg syndrome with intellectual disability, autistic spectrum disorder and unprovoked aggressive outbursts: a new behavioural phenotype? Br. J. Dev. Disabil. 53, 53–62 Edery P., Attie T., Amiel J. et al. (1996) Mutation of the endothelin3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat. Genet. 12, 442–444 National Health Service United Kingdom Genetic Testing Network [Online] http://www.ukgtn.nhs.uk/gtn/Search+for+a+Test/Search +by+Disease+or+Gene [accessed on 9 January 2012]

The Facial Artery musculomucosal flap revisited: surgical technique and critical functional appraisal: Our experience in nine patients van Weert, S. & Leemans, C.R. Department of Otolaryngology- Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands. Accepted for publication 13 September 2014

Dear Editor, Reconstruction of floor of mouth (FOM) defects following ablative tumour surgery is challenging in terms of function preservation. Different techniques are used such as a split skin graft (SSG) reconstruction, use of a nasolabial flap and healing by secondary intention. Split skin grafting has the disadvantage of a bolster in the mouth for several days and risk of loss of the grafted tissue. A SSG is unsuited for covering cortical bone. A nasolabial flap is a two-staged procedure and results in an external scar and relative bulk in the mouth with skin-lining and secondary hair growth intra-orally. Healing by secondary intention may cause contraction with tethering of the tongue. The advantages of the inferiorly based facial artery musculomucosal (FAMM) flap are adequate function preservation, no external scarring, low flap failure rate, low donor site morbidity, swift re-initiation of oral intake and a suitable mucosal lining with appropriate flap thickness that is very suitable in covering cortical bone. Correspondence: S. van Weert, Department of Otolaryngology- Head and Neck Surgery, VU University Medical Center, PO Box 7057 1007 MB Amsterdam, The Netherlands. Tel.: +3120-4443690; Fax: +3120-4443688; e-mail: [email protected]

This paper describes the surgical technique of the FAMM flap and analyses the functional outcome of the patients reconstructed with a FAMM flap for small- to medium-sized surgical defects of the anterior floor of mouth that include marginal mandibulectomy. Materials and methods Ethical considerations

Patients received a written invitation to participate in answering questionnaires and for undergoing functional tests. Informed consent was obtained prior to participation. Between January 2011 and December 2012, we performed nine FAMM flap reconstructions for small- to medium-sized floor of mouth defects after a marginal mandibulectomy. Patient data were collected with regard to age, gender, tumour localisation, T-stage, surgical margins, volume of the resected specimen, length of admission, time to nasogastric feeding tube removal, complication rate and functional recovery. Patients with pre-existing speech deficits, dysphagia or previous radiotherapy in the head and neck area were not included. © 2014 John Wiley & Sons Ltd  Clinical Otolaryngology 40, 41–64

Waardenburg syndrome: more common than you think!

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