A novel frameshift mutation in SOX10 causes Waardenburg syndrome with peripheral demyelinating neuropathy, visual impairment and the absence of Hirschsprung disease.

Waardenburg syndrome (WS) is a group of genetic disorders associated with varying components of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and eyes. There exist four different WS subtypes, each defined by the absence or presence of additional features. One of the genes associated with WS is SOX10, a key transcription factor for the development of neural crest-derived lineages. Here we report a 12-year-old boy with a novel de novo SOX10 frameshift mutation and unique combination of clinical features including primary peripheral demyelinating neuropathy, hearing loss and visual impairment but absence of Hirschsprung disease and the typical pigmentary changes of hair or skin. This expands the spectrum of currently recognized phenotypes associated with WS and illustrates the phenotypic heterogeneity of SOX10-associated WS.

Phenotypic similarities in pigs with SOX10c.321dupC and SOX10c.325A>T mutations implied the correlation of SOX10 haploinsufficiency with Waardenburg syndrome.

SOX10 is a causative gene of Waardenburg syndrome (WS) that is a rare genetic disorder characterized by hearing loss and pigment disturbance. More than 100 mutations of SOX10 have been found in patients with Type 2 WS (WS2), Type 4 WS (WS4), and more complex syndromes. However, no mutation hotspot has been detected in SOX10, and most cases are sporadic, making it difficult to establish a correlation between the high phenotypic and genetic variability. In this study, a duplication of the 321th cytosine (c.321dupC) was introduced into SOX10 in pigs, which induced premature termination of the translation of SOX10 (p.K108QfsX45). The premature stop codon in Exon 3 triggered the degradation of mutant mRNA through nonsense-mediated mRNA decay. However, SOX10c.321dupC induced a highly similar phenotype of WS2 with heterogeneous inner ear malformation compared with its adjacent missense mutation SOX10c.325A>T. In addition, a site-saturation mutation analysis of the SOX10 N-terminal nuclear localization signal (n-NLS), where these two mutations located, revealed the correlation between SOX10 haploinsufficiency and WS by an in vitro reporter assay. The analysis combining the in vitro assay with clinical cases may provide a clue to clinical diagnoses.

Degeneration of saccular hair cells caused by MITF gene mutation.

BACKGROUND: Waardenburg syndrome (WS) is the consequence of an inherited autosomal dominant mutation which causes the early degeneration of intermediate cells of cochlear stria vascularis (SV) and profound hearing loss. Patients with WS may also experience primary vestibular symptoms. Most of the current WS studies did not discuss the relationship between WS and abnormal vestibular function. Our study found that a spontaneous mutant pig showed profound hearing loss and depigmentation. MITF-M, a common gene mutation causes type WS which affect the development of the intermediate cell of SV, was then identified for animal modeling. RESULTS: In this study, the degeneration of vestibular hair cells was found in pigs with MITF-M. The morphology of hair cells in vestibular organs of pigs was examined using electron microscopy from embryonic day E70 to postnatal two weeks. Significant hair cell loss in the mutant saccule was found in this study through E95 to P14. Conversely, there was no hair cell loss in either utricle or semi-circular canals. CONCLUSIONS: Our study suggested that MITF-M gene mutation only affects hair cells of the saccule, but has no effect on other vestibular organs. The study also indicated that the survival of cochlear and saccular hair cells was dependent on the potassium release from the cochlear SV, but hair cells of the utricle and semi-circular canals were independent on SV.

A homozygous MITF mutation leads to familial Waardenburg syndrome type 4.

Waardenburg syndrome (WS) is a genetic disorder characterized by hearing loss and pigmentary abnormalities with variable penetrance. Though heterozygous mutations in MITF are a major cause for Waardenburg syndrome type 2 (WS2), homozygous mutations in this gene and the associated phenotype have been rarely characterized. In this study, we identified a novel p.R223H mutation in MITF in a Chinese Han family with variable WS features. Both parents carried a heterozygous p.R223H mutation. They had normal hearing, and premature greying of the hair is their only pigmentary abnormality. In contrast, their two children both carried a homozygous p.R223H mutation and had classic WS features including profound hearing loss, heterochromia irides and marked pigmentary abnormalities in hair and skin. Interestingly, the two affected children also have persistent chronic constipation since the neonatal period, symptoms suggestive of Waardenburg syndrome type 4 (WS4). Our study revealed a likely association between homozygous mutations in MITF and WS4, which implies a dosage effect for the underlying pathogenesis mechanism.

Homozygous EDNRB mutation in a patient with Waardenburg syndrome type 1.

OBJECTIVE: To examine and expand the genetic spectrum of Waardenburg syndrome type 1 (WS1). METHODS: Clinical features related to Waardenburg syndrome (WS) were examined in a five-year old patient. Mutation analysis of genes related to WS was performed in the proband and her parents. Molecular modeling of EDNRB and the p.R319W mutant was conducted to predict the pathogenicity of the mutation. RESULTS: The proband showed sensorineural hearing loss, heterochromia iridis, and dystopia canthorum, fulfilling the clinical criteria of WS1. Genetic analyses revealed that the proband had no mutation in PAX3 which has been known as the cause of WS1, but had a homozygous missense mutation (p.R319W) in endothelin receptor type B (EDNRB) gene. The asymptomatic parents had the mutation in a heterozygote state. This mutation has been previously reported in a heterozygous state in a patient with Hirschsprung's disease unaccompanied by WS, but the patient and her parents did not show any symptoms in gastrointestinal tract. Molecular modeling of EDNRB with the p.R319W mutation demonstrated reduction of the positively charged surface area in this region, which might reduce binding ability of EDNRB to G protein and lead to abnormal signal transduction underlying the WS phenotype. CONCLUSIONS: Our findings suggested that autosomal recessive mutation in EDNRB may underlie a part of WS1 with the current diagnostic criteria, and supported that Hirschsprung's disease is a multifactorial genetic disease which requires additional factors. Further molecular analysis is necessary to elucidate the gene interaction and to reappraise the current WS classification.

Neural tube defects in Waardenburg syndrome: A case report and review of the literature.

Waardenburg syndrome type 1 (WS1) is an autosomal dominant genetic condition characterized by sensorineural deafness and pigment abnormalities, and is caused by variants in the PAX3 homeodomain. PAX3 variants have been associated with severe neural tube defects in mice and humans, but the frequency and clinical manifestations of this symptom remain largely unexplored in humans. Consequently, the role of PAX3 in human neural tube formation remains a study of interest, for clinical as well as research purposes. Though the association between spina bifida and WS1 is now well-documented, no study has attempted to characterize the range of spina bifida phenotypes seen in WS. Spina bifida encompasses several diagnoses with a wide scope of clinical severity, ranging from spina bifida occulta to myelomeningocele. We present a patient with Waardenburg syndrome type 1 caused by a novel missense variant in PAX3, presenting with myelomeningocele, Arnold-Chiari malformation, and hydrocephalus at birth. Additionally, we review 32 total cases of neural tube defects associated with WS. Including this report, there have been 15 published cases of myelomeningocele, 10 cases of unspecified spina bifida, 3 cases of sacral dimples, 0 cases of meningocele, and 4 cases of miscellaneous other neural tube defects. Though the true frequency of each phenotype cannot be determined from this collection of cases, these results demonstrate that Waardenburg syndrome type 1 carries a notable risk of severe neural tube defects, which has implications in prenatal and genetic counseling.

Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation.

Waardenburg syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes.

Waardenburg-Shah Syndrome: a rare case in an Indian child.

A 7-year-old male child presented with a history of discolouration of right eye since birth. On examination visual acuity was 6/6 on Snellen's chart in both eyes; anterior segment was within normal limits except for the brilliant blue discolouration of the inferior quadrant and superior quadrant of right iris and left eye iris, respectively. Both eyes had a clear lens and fundus findings were within normal limits. A detailed history from parents revealed that the child had difficulty in hearing and slurring of speech. In addition, the child had repeated episodes of constipation with bilious vomiting during infancy for which a diagnosis of fungal sepsis with Hirschsprung's disease was made and the child had to undergo a mid-sigmoid loop colostomy for that. A diagnosis of Waardenburg--Shah Syndrome was made and the child was referred for hearing and speech rehabilitation.

The Hearing Outcomes of Cochlear Implantation in Waardenburg Syndrome.

Objectives. This study aimed to determine the feasibility of cochlear implantation for sensorineural hearing loss in patients with Waardenburg syndrome. Method. A retrospective chart review was performed on patients who underwent cochlear implantation at the University of Tokyo Hospital. Clinical classification, genetic mutation, clinical course, preoperative hearing threshold, high-resolution computed tomography of the temporal bone, and postoperative hearing outcome were assessed. Result. Five children with Waardenburg syndrome underwent cochlear implantation. The average age at implantation was 2 years 11 months (ranging from 1 year 9 months to 6 years 3 months). Four patients had congenital profound hearing loss and one patient had progressive hearing loss. Two patients had an inner ear malformation of cochlear incomplete partition type 2. No surgical complication or difficulty was seen in any patient. All patients showed good hearing outcome postoperatively. Conclusion. Cochlear implantation could be a good treatment option for Waardenburg syndrome.

Syndrome in Question.

Waardenburg syndrome is an inherited disease characterized by sensorineural hearing loss, pigmentation changes and minor facial malformations. It has four clinical variants. We report the case of a girl who, like her mother, was affected by this syndrome. The diagnosis was made after detection and treatment of deafness.

Syndrome in Question

AbstractWaardenburg syndrome is an inherited disease characterized by sensorineural hearing loss, pigmentation changes and minor facial malformations. It has four clinical variants. We report the case of a girl who, like her mother, was affected by this syndrome. The diagnosis was made after detection and treatment of deafness.

EPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndrome.

BACKGROUND: Waardenburg syndrome type I (WS1), an auditory-pigmentary genetic disorder, is caused by heterozygous loss-of-function mutations in PAX3. Abnormal physical signs such as dystopia canthorum, patchy hypopigmentation and sensorineural hearing loss are common, but short stature is not associated with WS1. CASE PRESENTATION: We reported a 4-year and 6 month-old boy with a rare combination of WS1 and severe short stature (83.5 cm (-5.8SD)). His facial features include dystopia canthorum, mild synophrys, slightly up-slanted palpebral fissure, posteriorly rotated ears, alae nasi hypoplasia and micrognathia. No heterochromia was noticed. He had a normal intelligence quotient and hearing. Insulin-like growth factor-1 (IGF-1) was 52.7 ng/ml, lower than the normal range (55 ~ 452 ng/ml) and the peak growth hormone level was 7.57 ng/ml at 90 minutes after taking moderate levodopa and pyridostigmine bromide. The patient exhibited a good response to human growth hormone (rhGH) replacement therapy, showing a 9.2 cm/year growth rate and an improvement of 1 standard deviation (SD) of height after one year treatment. CMA test of patient's DNA revealed a 4.46 Mb de novo deletion at 2q35-q36.2 (hg19; chr2:221,234,146-225,697,363). CONCLUSIONS: PAX3 haploinsufficiency is known to cause Waardenburg syndrome. Examining overlapping deletions in patients led to the conclusion that EPHA4 is a novel short stature gene. The finding is supported by the splotch-retarded and epha4 knockout mouse models which both showed growth retardation. We believe this rare condition is caused by the haploinsufficiency of both PAX3 and EPH4 genes. We further reported a growth response to recombinant human growth hormone treatment in this patient.

Clinical manifestations of Waardenburg syndrome in a male adolescent in Mali, West Africa.

Waardenburg syndrome (WS) is a genetic disorder of which there are four distinct types. These four types are differentiated by the physical defects which they produce. Presented here is the case of a 13-year-old boy with WS Type I who was observed and physically assessed in Mali, West Africa in 1969. His physical findings included a bright blue coloring to the irises of the eyes, profound sensorineural deafness, mutism, dystopia canthorum (lateral displacement of the inner canthi of the eyes), broad nasal root, bushy eyebrows, and scaphoid deformities of the supraorbital portions of the frontal bone. Because family members were not available for interviews or physical examinations, it was not possible to determine if this patient was suffering from a congenital form of the disorder or from a spontaneous mutation. Given the patient's then location in a remote rural area of Mali where electricity was absent, it was not possible to perform additional diagnostic tests. The patient described here is the first with WS in Mali, West Africa to have been medically observed and evaluated and later documented in the medical literature. A second case of the syndrome in Mali was described in the medical literature in 2011 in an 18-month-old infant who did not have sensorineural hearing loss, but who did have a bilateral cleft lip. An historical overview of WS is presented along with details concerning the characteristics of the four types of the disorder.

Waardenburg syndrome with familial unilateral renal agenesis: a new syndrome variant?

A 64-year-old man with Waardenburg syndrome presented with anuria and was subsequently discovered by renal ultrasound to have unilateral renal agenesis. The patient is one of three generations with incidental finding of renal agenesis also marked by the presence of Waardenburg syndrome. To our knowledge, there has been no mention elsewhere in the scientific literature of a variant of Waardenburg syndrome with associated renal agenesis.

Implante coclear en síndrome de Waardenburg: nuestra experiencia / Cochlear implant in Waardenburg syndrome: our experience / Implante coclear em síndrome de Waardenburg: nossa experiência

Introducción: El síndrome de Waardenburg hace referencia a un grupo de enfermedades hereditarias que aparecen como consecuencia de una alteración de la migración de células derivadas de la cresta neural entre la octava y décima semana de gestación. De ellas derivan melanocitos que migran a la estría vascular del órgano de Corti. Estos pacientes se caracterizan por presentar hipoacusia neurosensorial congénita de grado variable y alteraciones pigmentarias en piel, cabello y ojos. Su incidencia es de 1/42.000 habitantes y corresponde al 5% de hipoacusia neurosensorial sindrómica, siendo la causa más frecuente con patrón de herencia dominante. Método: Revisión de 4 pacientes menores de 18 años, con síndrome de Waardenburg asociado a hipoacusia neurosensorial severa a profunda, uni o bilateral, implantados en nuestro servicio. Se estudiaron todos los pacientes con audiometría tonal, logoaudiometría, potenciales evocados auditivos de tronco, tomografía computada y resonancia magnética. Además todos los pacientes contaban con estudio genético, psicodiagnóstico y seguimiento por pediatría, dermatología y oftalmología. Resultados: Todos nuestros pacientes presentaron telemetrías de impedancia normales, sus implantes fueron encendidos al mes postquirúrgico y en todos los casos se registraron buenos resultados audiológicos y mejoría en su calidad de vida. Conclusiones: Creemos importante conocer los aspectos básicos de esta patología para poder realizar una derivación pertinente y una atención en forma interdisciplinaria del paciente. La colocación de implantes cocleares en este grupo de pacientes con hipoacusia neurosensorial severa a profunda es satisfactorio.

Background: Waardenburg syndrome refers to agroup of inherited diseases that occur due to alteredmigration of cells derived from neural crest betweenthe eighth and tenth week of pregnancy. Ofthose derived melanocytes that migrate to the groovevascular organ of Corti. These patients are characterizedby congenital sensorineural hearing lossof variable degree and pigmentary changes in skin,hair and eyes. Its incidence is 1/42000 inhabitants and corresponds to 5% of syndromic sensorineuralhearing loss being the most common cause with dominantinheritance pattern. Method: Review of 4 patients under 18 years withWaardenburg syndrome associated with severeto profound sensorineural hearing loss, unilateralor bilateral, implanted in our service. All patientswere studied with audiometry, speech perceptiontest, brain stem auditory evoked responses, CT andMRI. Additionally, all patients had genetic testing,pedagogic evaluation and follow-up by pediatrics,dermatology and ophthalmology. Results: All our patients had normal impedancetelemetry, their implants were fired at postoperative month and in all cases good audiological resultsand improvement occurred in their quality of life.Conclusions: We believe that it’s important toknow the basics of this disease to make an appropriatereferral and interdisciplinary approach of the patient. Cochlear implants in this group of patientswith severe to profound sensorineural hearing lossis satisfactory.

Introdução: A síndrome de Waardenburg faz referência a um grupo de doenças hereditárias que aparecem como consequência de uma alteração da migração de células derivadas da crista neural entre a oitava e a décima semana de gestação. Delas derivam melanócitos que migram para a estria vascular do órgão de Corti. Estes pacientes se caracterizam por apresentar hipoacusia neurossensorial congênita de grau variável e alterações pigmentares na pele, cabelo e olhos. A incidência é de 1/42000 habitante-se corresponde a 5% de hipoacusia neurossensorial sindrômica sendo a causa mais frequente com padrão de herança dominante.Método: Revisão de 4 pacientes menores de 18anos, com síndrome de Waardenburg associada à hipoacusia neurossensorial severa a profunda, uniou bilateral, implantados no nosso serviço. Foram estudados todos os pacientes com audiometria tonal, logo audiometria, potenciais evocados auditivos de tronco, tomografia computadorizada e ressonância magnética. Além disso, todos os pacientes contavam com estudo genético, psicodiagnóstico e acompanhamento por pediatria, dermatologia e oftalmologia.Resultados: Todos os nossos pacientes apresentaram telemetrias de impedância normais, os seus implantes foram ligados um mês após a cirurgia e em todos os casos foram registrados bons resultados audiológicos e melhoria na sua qualidade de vida.Conclusões: Acreditamos que seja importante conhecer os aspectos básicos desta patologia para poder realizar uma derivação pertinente e um atendimento interdisciplinar do paciente. A colocação de implantes cocleares neste grupo de pacientes com hipoacusia neurossensorial severa a profunda é satisfatória.

Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome.

The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes.

Double heterozygous mutations of MITF and PAX3 result in Waardenburg syndrome with increased penetrance in pigmentary defects.

Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentary defects of the hair, skin, and iris. Heterozygous mutations of MITF and its transactivator gene PAX3 are associated with Waardenburg syndrome type II (WS2) and type I (WS1), respectively. Most patients with MITF or PAX3 mutations, however, show variable penetrance of WS-associated phenotypes even within families segregating the same mutation, possibly mediated by genetic background or specific modifiers. In this study, we reported a rare Waardenburg syndrome simplex family in which a pair of WS parents gave birth to a child with double heterozygous mutations of MITF and PAX3. Compared to his parents who carried a single mutation in either MITF or PAX3, this child showed increased penetrance of pigmentary defects including white forelock, white eyebrows and eyelashes, and patchy facial depigmentation. This observation suggested that the expression level of MITF is closely correlated to the penetrance of WS, and variants in transcription regulator genes of MITF may modify the relevant clinical phenotypes.

Don't it make my blue eyes brown: heterochromia and other abnormalities of the iris.

Eye colour is one of the most important characteristics in determining facial appearance. In this paper I shall discuss the anatomy and genetics of normal eye colour, together with a wide and diverse range of conditions that may produce an alteration in normal iris pigmentation or form.