Waardenburg Syndrome Research Articles

Novel Splice Mutation in Microthalmia-Associated Transcription Factor in Waardenburg Syndrome

Waardenburg Syndrome (WS) is a syndromic form of hearing loss associated with mutations in six different genes. We identified a large family with WS that had previously undergone clinical testing, with no reported pathogenic mutation. Using linkage analysis, a region on 3p14.1 with an LOD score of 6.6 was identified. Microthalmia-Associated Transcription Factor, a gene known to cause WS, is located within this region of linkage. Sequencing of Microthalmia-Associated Transcription Factor demonstrated a c.1212 G>A synonymous variant that segregated with the WS in the family and was predicted to cause a novel splicing site that was confirmed with expression analysis of the mRNA. This case illustrates the need to computationally analyze novel synonymous sequence variants for possible effects on splicing to maximize the clinical sensitivity of sequence-based genetic testing.

PAX3 (paired box gene 3 (Waardenburg syndrome 1))

Review on PAX3 (paired box gene 3 (Waardenburg syndrome 1)), with data on DNA, on the protein encoded, and where the gene is implicated.

Asymmetric severity of diabetic retinopathy in Waardenburg syndrome

A 30-year-old female patient was referred to our institution due to vitreous hemorrhage. Best corrected visual acuity of her right and left eyes at her initial visit was 10/20 and 20/20, respectively. Although hypochromic iris was observed in the superior iris between the 10 and 2 o’clock positions in her right eye, her entire left eye exhibited hypochromic iris. Hypopigmentation of the fundus was seen in the superior part of her right eye. This eye also had a huge neovascularization on the optic disc that was 7 discs in diameter. Conversely, her left fundi showed hypopigmentation of the fundus in the entire region of the left eye, and dot hemorrhages were observed all over the left fundi, although no neovascularization could be seen microscopically. Fluorescein angiography showed a huge neovascularization in the right eye and a tiny neovascularization in the left eye. Gene analysis revealed the presence of the PAX3 gene homeobox domain mutation, which led to her being diagnosed as Waardenburg syndrome type 1. Magnetic resonance angiography showed there was no obstructive region at either of the internal carotid arteries and ophthalmic arteries. The severity of the diabetic retinopathy appeared to be correlated with the degree of hypopigmentation in the posterior fundus. We speculate that hypopigmentation of the fundus in Waardenburg syndrome may be responsible for the reduction in retinal metabolism, which led to a reduction in oxygen consumption and prevented further aggravation of the diabetic retinopathy. Only laser treatments using short wavelengths was effective in this case. While the extinction coefficient for hemoglobin when using green light is higher than when using yellow light, the differences between these wavelengths tend to disappear when oxygenated hemoglobin is present. To the best of the authors’ knowledge, this is the first case report of a patient with Waardenburg syndrome and diabetic retinopathy.

Waardenburg syndrome type I- a rare case report

Waardenburg syndrome (WS) is an inherited autosomal dominant disorder characterized by varying degrees of hearing loss and pigmentary anomalies affecting the eye, hair, skin. It is a rare syndrome affecting about 1 in 42,000 individuals. We herein report a case of WS type I in an 8 day old neonate, which to the best knowledge of the authors is the youngest reported case in literature.

İşitme Engelliler Okulundaki Çocuklarda Göz Sağlığı Taraması

Objective: The aim of this study was to screen the ophthalmic disorders in a school for the hearing impaired and to draw the attention to the necessity of early educational and career modifications of children with Usher syndrome. Material and Methods: The study population was 208 of 214 students in a school for hearing impaired in Ankara; ages ranged from 7 to 19 years. All students underwent an ophthalmologic examination, including uncorrected and corrected visual acuity measurement, assessment of manifest refraction, slit lamp biomicroscopy and fundoscopy. Cover/uncover test was done to detect a tropia of more than 10 prism diopters. Students with an ophthalmic pathology were invited for a detailed eye examination. Chi square test and binary logistic regression analysis were used for statistical analysis. Results: Of the 208 students, 72 (34.6%) had an ocular abnormality. One hundred eighty four (88.5%) children presented with normal fundus findings. Of the 24 patients with an ophthalmoscopic finding, twelve (5.8%) were diagnosed with retinitis pigmentosa, three with Waardenburg syndrome and four with atypical retinal pigmentary changes. Female gender (p< 0.05) and the presence of a refractive error (p< 0.0001) were significantly correlated with the existence of ophthalmoscopic findings. Conclusion: Early referral to an ophthalmic examination is mandatory for the hearing impaired children. In previous studies, higher frequency of ophthalmic disorders in the hearing impaired population had been reported; present study also emphasizes the necessity of educational and career modifications in hearing impaired children with retina pathologies. Detection and early intervention of ophthalmologic abnormalities is important for the normal development of cognitive and social skills and also for education and career modifications.

Ophthalmologic abnormalities among deaf students in Kaduna, Northern Nigeria

The association between deafness and ocular problems is well established; however the nature and prevalence of these problems are diverse across the globe. The aim of this study is to determine the nature and prevalence of ophthalmologic abnormalities in deaf students and offer treatment to those with remediable conditions. Six hundred and twenty deaf students aged between 5 and 38 years were examined in a school for the deaf. One hundred and thirty (20.9%) had some form of ophthalmologic abnormality. Some had anterior segment abnormalities such as corneal opacities (0.5%) and allergic conjunctivitis (3.4%) while others had posterior segment abnormalities like optic atrophy (0.3%), Waardenburg syndrome (0.6%) and Ushers syndrome (0.6%). Refractive error was the most common (7.9%). Since these deaf students use their sight to compensate for the deafness, routine ophthalmologic examination should be carried out on them so that ophthalmologic abnormalities are detected early and treatment offered for remediable diseases.

Conversion Disorder

To report a case of a patient presenting with presumed cochlear implant (CI) device failure that underwent revision surgery and was ultimately diagnosed with conversion disorder. Clinical capsule report. Tertiary academic referral center. A pediatric patient with Waardenburg syndrome underwent unilateral CI at the age of 6 years for bilateral profound sensorineural hearing loss. During the following 2 years, the patient experienced subjective symptoms of device malfunction including abnormal sounds and intermittent loss of signal despite external component exchange. The patient subsequently underwent revision surgery only to have persistent intermittent complaints. Given the severity of the symptoms, the patient underwent a second reimplantation procedure. Extensive device testing by our institutional implant program and the manufacturer failed to reveal any causal device defects. Given the ongoing but inconsistent subjective complaints and normal device testing, the patient was referred for psychiatric consultation to evaluate for a nonorganic underlying cause. The patient was subsequently diagnosed with conversion disorder and successfully managed with ongoing psychiatric counseling and close follow-up with our CI program. This represents the first report of a patient presenting with symptoms of device failure, who underwent revision surgery and was ultimately found to have conversion disorder. Although rare, conversion disorder should be considered in the differential diagnosis of patients presenting with symptoms of device malfunction and normal integrity testing particularly among those with significant psychosocial stressors or a history of psychiatric illness. Thorough device testing and in-depth psychological evaluation is required for diagnosis, and close multidisciplinary follow-up with the CI team and psychiatrist is crucial.

Audiometric Findings in Waardenburg's Syndrome Amongst the Institutionalised Deaf / Blind in Kaduna-Nigeria

Waardenburg's syndrome is a rare inherited disorder of congenital hearing loss and Pigmentary disturbances of the eyes, hair, skin and neural crest derivatives. 620 students in a deaf/blind school were examined end four had Waardenburg's syndrome with a frequency of 0.65%. 2 males and 2 females with Waardenburg's syndrome and age ranges between 1019 years (mean 15.75 years) All 4 subjects had complete blue irides, white forelock and sensorineural hearing loss, and thus met the diagnostic criteria. They were then subjected to Audiometric assessment. Otoscopy was essentially normal but Audiometry revealed sensorineural hearing loss [SNHL] in all the subjects ranging from severe to profound with one subject being stone deaf. Waardenburg's syndrome is a rare disorder in our environment although it may be under reported. Two of the subjects benefited from amplification and were given hearing Aids. Provision of early amplification cannot be over emphasized.

Delayed Presentation of Children with Waardenburg Syndrome

Delayed Presentation of Children with Waardenburg Syndrome

P18. Sox10 mutation affects enteric neural crest cell migration in a cell autonomous manner

Enteric neural crest stem cells (eNCSCs) are a pluripotent, migratory cell population that gives rise to the enteric neurons and glia throughout the gastrointestinal tract. Sox10 is a transcription factor required for the maintenance of pluripotency and survival of eNCSCs during enteric nervous system (ENS) development. SOX10 mutations disrupt NCSCs development and result in Waardenburg–Hirschsprung (WS4) disease, which displays varying degrees of intestinal aganglionosis, pigmentation and hearing defects. To elucidate the role of Sox10 in migration of eNCSCs, and to understand how the impaired function contributes to gut aganglionosis, we generated a novel WS4 mouse mutant Sox10NGFP where EGFP reporter was fused to the N-terminal region of Sox10 . EGFP expression in Sox10NGFP mice recaptured the dynamics of Sox10 expression during development. Neurospheres of mutant eNCSCs exhibited reduced proliferation capability as demonstrated by BrdU incorporation assay. The mean size of mutant neurospheres was significantly reduced compared with wildtype control. Using time-lapse imaging, we found that migratory eNCSCs in Sox10NGFP/+ mutants displayed altered trajectories and reduced migration speed compared to Wnt1cre/ZEG control. Explant culture, assays that determine the advancement of eENCCs in normal/abnormal gut environment, indicated that migration defects in Sox10NGFP/+ mice occurred in a cell-autonomous manner. Together, these findings suggested that Sox10 mutation impaired the proliferation and migration capability of eNCSCs. The abnormal migration behavior of mutant eNCSCs restricted the colonization of eNCSC along the gut wall, and contributed to aganglionosis in mutant guts.

50 Years Ago in T he J ournalof P ediatrics: Waardenburg's Syndrome: A Syndrome of Heterochromia of the Irides, Lateral Displacement of the Medial Canthi, and Lacrimal Puncta, Congenital Deafness, and Other Characteristic Associated Defects

50 Years Ago in T he J ournalof P ediatrics: Waardenburg's Syndrome: A Syndrome of Heterochromia of the Irides, Lateral Displacement of the Medial Canthi, and Lacrimal Puncta, Congenital Deafness, and Other Characteristic Associated Defects

Effect of the Mutant Microphthalmia-Associated Transcription Factor Found in Tietz Syndrome on the In Vitro Development of Mast Cells

Mutations in microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome type 2 (WS2), a dominantly inherited disorder involving hearing loss and pigment disturbances caused by a lack of melanocytes. On rare occasions, mutations in MITF lead to Tietz syndrome (TS), which is characterized by a severe WS2 phenotype. The MITF gene is the human homolog of the mouse microphthalmia (mi) gene in some families. Mi/mi mice show decreased numbers and an abnormal phenotype of mast cells (MC). In contrast, the number and phenotype of MC in WS2/TS patients who also have an alteration in their MITF gene are unclear. In this study, we identified a mutation in the MITF gene, delR217, which was equivalent to that found in mi/mi mice, in a case of TS. None of the MITF isoforms with the mutation were able to transactivate the tyrosinase gene promoter. In addition, mutant MITF-M showed dominant negative activity toward wild-type MITF-M, inhibiting its transactivation of the tyrosinase gene promoter. The patient's peripheral blood CD34 cells showed no differences with respect to total cell number or their expression levels of tryptase mRNA in a serum-deprived liquid culture system for 6 weeks when compared with normal control cells. These findings suggest that MITF does not play a critical role in MC development in humans.

The PAX3 Paired Domain and Homeodomain Function as a Single Binding Module In Vivo to Regulate Subnuclear Localization and Mobility by a Mechanism That Requires Base-Specific Recognition

The transcription factor PAX3 is essential for myogenesis and neural crest development, and is one of several genes mutated in human Waardenburg syndrome. Analysis of disease-causing missense mutations in PAX3 has established the interdependence of its two DNA-binding domains, the paired domain (PD) and the homeodomain (HD), as well as defects in localization and mobility. Paradoxically, mutants that retained DNA binding activity exhibited the greatest defects in localization and mobility, regardless of the domain in which they reside. In the present study, structure–function analyses were used to determine the mechanistic basis of this effect. In the context of the isolated DNA-binding domains, HD mutants adopted an increase in mobility proportional to their loss in DNA binding, while PD mutants continued to display the inverse relationship observed in the full-length protein. At the structural level, this reflected an unexpected dependence on base-specific contacts in the PD, whereas HD mobility was more severely affected by loss of backbone contacts, as has been observed with other DNA-binding proteins. This requires that the HD switch to a base-specific mode in the full-length protein. Moreover, both domains underwent substantial reduction in mobility and altered localization when in a contiguous polypeptide with the endogenous linker segment. Notably, although the HD conferred localization to heterochromatin, this activity was masked when linked to the PD, despite the absence of determinants for subnuclear compartmentalization in the PD or linker. Last, the propensity for PAX3 heterochromatin localization was modulated by sequences at the amino and carboxy termini, supporting a model in which alternate conformations lead to unmasking of the HD. These data indicate that the PD and the HD functionally interact in vivo and behave as a single binding module whose mobility and localization are dependent on sequence-specific contacts.

Slug, mammalian homologue gene of Drosophila escargot, promotes neuronal-differentiation through suppression of HEB/daughterless

At the neuron developmental stage, neuron-precursor cells can be differentiated into neuron or glia cells. However, precise molecular mechanism to determine the cell fate has not been clearly demonstrated. In this study, we reveal that Drosophila esgarcot and its mammalian homologue genes, Snail and Slug, play a key role in neuronal differentiation. In Drosophila model system, overexpression of Esg, like as Wingless, suppresses the bristle formation. In contrast, elimination of Esg though RNAi promotes double bristle phenotype. We can also observe the similar phenotype in Snail-overexpression system. In mammalian system, overexpression of Slug or Snail can induce neuronal differentiation. Esg and its mammalian homologue gene Slug directly interact with Daughtherless and its mammalian homologue HEB and eliminate them through siah-1 mediated protein degradation. Thus, overexpression of siah-1 can promote neuron cell differentiation, whereas si-siah-1 blocks the Slug-induced HEB suppression. In fact, Drosophila SINA, Siah-1 homologue, has been also known to be involved in bristle formation and Neuronal differentiation. In addition, it has been revealed that CK1 is involved in Esg or Snail stability and Neuronal differentiation. However, Snail is regulated only by CK1 but not by Siah. Considering the fact that Slug mutations have been found in human genetic disease, waardenberg syndrome, major symptoms of which is loss of hearing neuron and odd eye, our result implies that Slug/Snail system is required for proper neuronal differentiation, like as Esg in Drosophila.

Genetisch bedingte Pigmentstörungen

Pigmentation in human skin differs individually and is regulated by more than 100 genes. The discovery of an increasing number of these genes has shed light on the molecular basis and pathogenesis of genetic pigmentary disorders. They are very rare and can be caused by changes in melanocyte number or melanin synthesis as well as development, transport and transfer of melanosomes. Pigmentary disorders can be divided into hyper- and hypopigmentation, of which the distribution can be diffuse or localized. Localized hypopigmentation can be found in piebaldism, Waardenburg syndrome and Tietz syndrome, whereas diffuse forms are typical for oculocutaneous albinism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome and Griscelli syndrome. Hyperpigmentation can be divided into diffuse, reticular or localized forms. They must be distinguished from endocrinopathies which may show hyperpigmentation, and from poikilodermatous syndromes displaying internal involvement.

Permanent Poliosis following Repetitive Plucking in an Adolescent

poliosis is an inherited or acquired loss of pigment from a group of closely positioned hair follicles characterized by a patch of white hair. It is commonly seen in vitiligo, piebaldism, Waardenburg syndrome, Vogt-Koyanagi-Harada syndrome, Griscelli syndrome, and Apert syndrome. We investigated a male manifesting poliosis on the chin after repetitive plucking. to our knowledge, poliosis induced by repeated plucking has never been documented.

Perturbation of the consensus activation site of endothelin‐3 leads to Waardenburg syndrome type IV

Perturbation of the consensus activation site of endothelin‐3 leads to Waardenburg syndrome type IV

P160 THE PREVELANCE OF SUBCLINICAL HYPOTHYROIDISM AMONG PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

MITF mutations results in an abnormal melanocyte development and lead to Waardenburg syndrome type 2 (WS2). Here, we analyzed the in vitro activities of two recently identified WS2-associated MITF mutations (p.R217I and p.T192fsX18). The R217I MITF retained partial activity, normal DNA-binding ability and nuclear distribution, whereas the T192fsX18 MITF failed to activate TYR promoter and showed aberrant subcellular localization which may be caused by deletion of nuclear localization signal (NLS) at aa 213–218 (ERRRRF). These results suggest that haploinsufficiency may be the underlying mechanism for the mild phenotypes of WS2 caused by these two mutations.

Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome

Waardenburg syndrome (WS) is a rare disorder characterized by distinctive facial features, pigment disturbances, and sensorineural deafness. There are four WS subtypes. WS1 is mostly caused by PAX3 mutations, while MITF, SNAI2, and SOX10 mutations are associated with WS2. More than 100 different disease-causing mutations have been reported in many ethnic groups, but the data from Chinese patients with WS remains poor. Herein we report 18 patients from 15 Chinese WS families, in which five cases were diagnosed as WS1 and the remaining as WS2. Clinical evaluation revealed intense phenotypic variability in Chinese WS patients. Heterochromia iridis and sensorineural hearing loss were the most frequent features (100% and 88.9%, respectively) of the two subtypes. Many brown freckles on normal skin could be a special subtype of cutaneous pigment disturbances in Chinese WS patients. PAX3, MITF, SNAI2, and SOX10 genes mutations were screened for in all the patients. A total of nine mutations in 11 families were identified and seven of them were novel. The SOX10 mutations in WS2 were first discovered in the Chinese population, with an estimated frequency similar to that of MITF mutations, implying SOX10 is an important pathogenic gene in Chinese WS2 cases and should be considered for first-step analysis in WS2, as well as MITF.

Cochlear implantation in Waardenburg syndrome: The Indian scenario

Conclusion: Children with Waardenburg syndrome (WS) exhibiting normal inner ear anatomy, like those included in our cohort, derive significant benefit from cochlear implantation and results are comparable to those reported for the general population of implanted children. Objectives: The patient population of WS accounts for approximately 2% of congenitally deaf children. The purpose of this retrospective case review was to describe the outcomes for those children with WS who have undergone cochlear implantation. Methods: On retrospective chart review, there were four cases with WS who underwent cochlear implantation. These cases were assessed for age at implantation, clinical and radiological features, operative and perioperative course, and performance outcomes. Auditory perception and speech production ability were evaluated using categories of auditory performance (CAP), meaningful auditory integration scales (MAIS), and speech intelligibility rating (SIR) during the follow-up period. Results: In this group of children with WS, with a minimum follow-up of 12 months, the CAP score ranged from 3 to 5, MAIS from 25 to 30, and SIR was 3. These scores are comparable with those of other cochlear implantees.