Waardenburg Syndrome Research Articles

Childhood Hearing Impairment in Senegal.

We recently showed that variants in GJB2 explained Hearing Impairment (HI) in 34.1% (n = 15/44) of multiplex families in Senegal. The present study aimed to use community-based nationwide recruitment to determine the etiologies and the clinical profiles of childhood HI in Senegal. Participants with early onset HI were included after clinical examination, including audiological assessment by pure tone audiometry and/or auditory brainstem response. We investigated a total of 406 participants from 295 families, recruited from 13/14 administrative regions of Senegal. Male/female ratio was 1.33 (232/174). Prelingual HI was the most common type of HI and accounted for 80% (n = 325 individuals). The mean age at medical diagnosis for congenital HI was computed at 3.59 ± 2.27 years. Audiological evaluation showed sensorineural HI as the most frequently observed HI (89.16%; n = 362 individuals). Pedigree analysis suggested autosomal recessive inheritance in 61.2% (63/103) of multiplex families and sporadic cases in 27 families (26.2%; 27/103), with a consanguinity rate estimated at 93% (84/90 families). Genetic factors were likely involved in 52.7% (214/406) of the cases, followed by environmental causes (29.57%; 120/406). In 72 cases (17.73%), the etiology was unknown. Clinically, non-syndromic HI was the most common type of HI (90.6%; n = 194/214 individuals). Among families segregating syndromic cases, type 2 Waardenburg syndrome was the most common (36.3%; 4/11 families). This study revealed putative genetic factors, mostly associated with high consanguinity rate, as the leading causes of early-onset HI in Senegal. The high consanguinity could provide a good opportunity to identify variants in known and novel genes involved in childhood HI.

Analysis of molecular genetics and clinical characteristics of 3 children with Waardenburg syndrome

Objective:To analyze the molecular genetics and clinical characteristics of 3 children with syndromic deafness were analyzed to clarify their causative genes and genetic characteristics. Methods:The medical records of 3 children and their parents were collected and analyzed, including physical examination, hearing evaluation, temporal bone CT, and cranial MRI. Whole-exome sequencing（WES） was used to screen for pathogenic gene variants, and Sanger sequencing was used to verify the candidate positive variants in the probands and their parents. Results:All 3 patients were female with normal intelligence. Patient 1 and 3 had a family history of deafness, which conformed to the pattern of autosomal dominant inheritance. All three patients had bilateral profound sensorineural hearing impairment with bright-blue sclera. Other phenotypes included hypertelorism（patient 1）, multiple dyschromatosis（patient 2）, and yellowish hair（patient 2）, blepharoptosis（patient 3）. Patient 3 had bilateral vestibular enlargement, internal auditory canal enlargement, and bilateral inner ear malformations. Mother of patient 1 had only left mild hearing impairment; mother of patient 3 had bilateral hearing impairment with unilateral bright-blue sclera and yellowish hair. WES detected heterozygous variants, PAX3 c.811C>T, MITF c.632T>C, and SOX10 c.1359_1360 insGCCCCACA, in patient 1, 2, and 3, respectively. The variants in patient 1 and 3 were inherited from their mothers who had hearing impairment, and MITFvariant in patient 2 may be a spontaneous variation. The final diagnoses were that patient 1 with Waardenburg syndrome type 1（WS1）, and the mother of patient 1, patient 2, patient 3, and the mother of patient 3 with WS2. Conclusion:WS is a syndromic deafness, and the main clinical features include autosomal dominant inheritance and scleral pigment abnormalities. However, the findings of this study show that there is still phenotypic heterogeneity in WS even caused by the same gene variant, so it depends on genetic tests to confirm the diagnosis; The gene variant of patient 1 and 2 was never been reported in other patients, which expands the pathogenic variant spectrum of WS.

A unique hyperdynamic dimer interface permits small molecule perturbation of the melanoma oncoprotein MITF for melanoma therapy.

Microphthalmia transcription factor (MITF) regulates melanocyte development and is the "lineage-specific survival" oncogene of melanoma. MITF is essential for melanoma initiation, progression, and relapse and has been considered an important therapeutic target; however, direct inhibition of MITF through small molecules is considered impossible, due to the absence of a ligand-binding pocket for drug design. Here, our structural analyses show that the structure of MITF is hyperdynamic because of its out-of-register leucine zipper with a 3-residue insertion. The dynamic MITF is highly vulnerable to dimer-disrupting mutations, as we observed that MITF loss-of-function mutations in human Waardenburg syndrome type 2 A are frequently located on the dimer interface and disrupt the dimer forming ability accordingly. These observations suggest a unique opportunity to inhibit MITF with small molecules capable of disrupting the MITF dimer. From a high throughput screening against 654,650 compounds, we discovered compound TT-012, which specifically binds to dynamic MITF and destroys the latter's dimer formation and DNA-binding ability. Using chromatin immunoprecipitation assay and RNAsequencing, we showed that TT-012 inhibits the transcriptional activity of MITF in B16F10 melanoma cells. In addition, TT-012 inhibits the growth of high-MITF melanoma cells, and inhibits the tumor growth and metastasis with tolerable toxicity to liver and immune cells in animal models. Together, this study demonstrates a unique hyperdynamic dimer interface in melanoma oncoprotein MITF, and reveals a novel approach to therapeutically suppress MITF activity.

Waardenburg Syndrome with Rare Ocular Features

Introduction: Waardenburg syndrome (WS) is an uncommon autosomally inherited disease with four subtypes. Case Report: We report a case of a 5-year-old girl with molluscum contagiosum with features of Waardenburg syndrome with dystopia canthorum, synophrys, broad nasal root, and sensorineural hearing loss. Discussion: The association between Waardenburg syndrome and ocular albinism is rare and hence reported.

Síndrome de Waardenburg: relato de caso de criança e seu grupo familiar em uma Unidade Básica de Saúde

Síndrome de Waardenburg: relato de caso de criança e seu grupo familiar em uma Unidade Básica de Saúde

Waardenburg syndrome: case report of a child and his family group in a Health Unity

Waardenburg syndrome: case report of a child and his family group in a Health Unity

Waardenburg syndrome complicated by osteosarcoma: A rare case report

Waardenburg syndrome complicated by osteosarcoma: A rare case report

Quantitative assessment of low-level parental mosaicism of SNVs and CNVs in Waardenburg syndrome.

Waardenburg syndrome (WS) is a rare inherited autosomal dominant disorder caused by SOX10, PAX3, MITF, EDNRB, EDN3, and SNAI2. A large burden of pathogenic de novo variants is present in patients with WS, which may be derived from parental mosaicism. Previously, we retrospectively analyzed 90 WS probands with family information. And the frequency of de novo events and parental mosaicism was preliminary investigated in our previous study. In this study, we further explored the occurrence of low-level parental mosaicism in 33 WS families with de novo variants and introduced our procedure of quantifying low-level mosaicism. Mosaic single nucleotide polymorphisms (SNPs) were validated by amplicon-based next-generation sequencing (NGS); copy-number variants (CNVs) were validated by droplet-digital polymerase chain reaction (ddPCR). Molecular validation of low-level mosaicism of WS-causing variants was performed in four families (12.1%, 4/33). These four mosaic variants, comprising three SNVs and one CNV, were identified in SOX10. The rate of parental mosaicism was 25% (4/16) in WS families with de novo SOX10 variants. The lowest allele ratio of a mosaic variant was 2.0% in parental saliva. These de novo WS cases were explained by parental mosaicism conferring an elevated recurrence risk in subsequent pregnancies of parents. Considering its importance in genetic counseling, low-level parental mosaicism should be systematically investigated by personalized sensitive testing. Amplicon-based NGS and ddPCR are recommended to detect and precisely quantify the mosaicism for SNPs and CNVs.

Hereditary hearing loss

Understanding the genetic basis of hearing loss is becoming increasingly relevant, as 50-70% of congenital hearing loss is hereditary and postlingual hearing loss is also often of hereditary origin. To date, more than 220genes for hearing loss have been identified and more than 600syndromes with hearing loss described. This review article explains the classification of genetic hearing loss into syndromic versus non-syndromic forms and the modes of inheritance involved. Some of the most common syndromes (Usher, Pendred, Jervell-Lange-Nielsen, Waardenburg, branchiootorenal, and Alport syndrome) are introductorily described. New sequencing technologies have significantly expanded the diagnostic options for genetic hearing loss and made them more accessible. This text aims to encourage initiation of genetic diagnosis in hearing-impaired patients with suspected hereditary genesis in order to provide the best possible counseling for affected individuals and their families.

Ocular Manifestations in Patients with Sensorineural Hearing Loss.

Identification of ocular manifestations in patients with sensorineural hearing loss (SNHL) can have a large impact on the outcome and treatment of pediatric patients. Due to the common co-incidence of ocular manifestations and SNHL in children, both ophthalmologic and hearing loss screening and routine examinations must be conducted to minimize adverse outcomes and worsening of pathology. Early evaluation and diagnosis is imperative for intervention and further development of the patient. Co-incidence requires a thorough evaluation that includes a comprehensive history, examination, and diagnostic testing. In this article, a literature review was conducted to analyze the presentations of various diseases and syndromes, such as Alport Syndrome, Waardenburg Syndrome, Norrie Disease, Usher Disease, Stickler Syndrome, Marfan Syndrome, Congenital Rubella, and Hereditary Optic Neuropathies. We divided the various ocular pathologies into anterior and posterior segment presentations and associated systemic findings for better understanding. Additionally, this review aims to include an update on the management of patients with both ocular and hearing loss manifestations.

Identification of nine novel variants across PAX3, SOX10, EDNRB, and MITF genes in Waardenburg syndrome with next-generation sequencing.

Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. A total of 24 patients from 21 Han-Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next-generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.

A comprehensive genotype–phenotype evaluation of eight Chinese probands with Waardenburg syndrome

BackgroundWaardenburg syndrome (WS) is the most common form of syndromic deafness with phenotypic and genetic heterogeneity in the Chinese population. This study aimed to clarify the clinical characteristics and the genetic cause in eight Chinese WS families (including three familial and five sporadic cases). Further genotype–phenotype relationships were also investigated.MethodsAll probands underwent screening for the known WS-related genes including PAX3, SOX10, MITF, EDNRB, EDN3, and SNAI2 using next-generation sequencing to identify disease-causing genes. Further validation using Sanger sequencing was performed. Relevant findings for the associated genotype–phenotype from previous literature were retrospectively analyzed.ResultDisease-causing variants were detected in all eight probands by molecular genetic analysis of the WS genes (SOX10(NM_006941.4): c.544_557del, c.553 C > T, c.762delA, c.336G > A; MITF(NM_000248.3): c.626 A > T; PAX3(NM_181459.4): c.838delG, c.452-2 A > G, c.214 A > G). Six mutations (SOX10:c.553 C > T, c.544_557del, c.762delA; PAX3: c.838delG, c.214 A > G; MITF:c.626 A > T) were first reported. Clinical evaluation revealed prominent phenotypic variability in these WS patients. Twelve WS1 cases and five WS2 cases were diagnosed in total. Two probands with SOX10 mutations developed progressive changes in iris color with age, returning from pale blue at birth to normal tan. Additionally, one proband had a renal malformation (horseshoe kidneys).All cases were first described as WS cases. Congenital inner ear malformations were more common, and semicircular malformations were exclusively observed in probands with SOX10 mutations. Unilateral hearing loss occurred more often in cases with PAX3 mutations.ConclusionOur findings helped illuminate the phenotypic and genotypic spectrum of WS in Chinese populations and could contribute to better genetic counseling of WS.

Waardenburg syndrome associated neurotrophic keratopathy in a child treated with neurotization surgery

Waardenburg syndrome (WS) is a genetic disorder characterized by congenital sensorineural hearing loss and pigmentary anomalies in the iris, hair, and skin. Ocular findings in WS include telecanthus, iris heterochromia, congenital cataracts, dry eye, and strabismus. To our knowledge, we report the first case of neurotrophic cornea in a patient with WS.

NR2F1 regulates a Schwann cell precursor-vs-melanocyte cellfate switch in a mouse model of Waardenburg syndrome type IV.

Waardenburg syndrome type 4 (WS4) combines abnormal development of neural crest cell (NCC)-derived melanocytes (causing depigmentation and inner ear dysfunction) and enteric nervous system (causing aganglionic megacolon). The full spectrum of WS4 phenotype is present in Spot mice, in which an insertional mutation close to a silencer element leads to NCC-specific upregulation of the transcription factor-coding gene Nr2f1. These mice were previously found to develop aganglionic megacolon because of NR2F1-induced premature differentiation of enteric neural progenitors into enteric glia. Intriguingly, this prior work also showed that inner ear dysfunction in Spot mutants specifically affects balance but not hearing, consistent with the absence of melanocytes in the vestibule only. Here, we report an analysis of the effect of Nr2f1 upregulation on the development of both inner ear and skin melanocytes, also taking in consideration their origin relative to the dorsolateral and ventral NCC migration pathways. In the trunk, we found that NR2F1 overabundance in Spot NCCs forces dorso-laterally migrating melanoblasts to abnormally adopt a Schwann cell precursor (SCP) fate and conversely prevents ventrally migrating SCPs to normally adopt a melanoblast fate. In the head, Nr2f1 upregulation appears not to be uniform, which might explain why SCP-derived melanocytes do colonize the cochlea while non-SCP-derived melanocytes cannot reach the vestibule. Collectively, these data point to a key role for NR2F1 in the control of SCP-vs-melanocyte fate choice and unveil a new pathogenic mechanism for WS4. Moreover, our data argue against the proposed existence of a transit-amplifying compartment of melanocyte precursors in hair follicles.

Waardenburg syndrome type 4 coexisting with open-angle glaucoma: a case report

BackgroundWaardenburg syndrome is an autosomal dominant disorder with varying degrees of sensorineural hearing loss as well as abnormal pigmentation in hair, skin, and iris. There are four types of Waardenburg syndrome (1–4) with different characteristics. Mutations in six genes have been identified to be associated with the various types. Herein, we describe a case of Waardenburg syndrome type 4 combined with open-angle glaucoma.Case presentationA 43-year-old Han Chinese man had undergone trabeculectomy due to progression of visual field impairment and unstable intraocular pressure in both eyes. Slit-lamp examination revealed diffuse iris hypopigmentation in the left eye and hypopigmentation of part of the iris in the right eye. Fundus examination showed red, sunset-like fundus due to a lack of pigmentation in the retinal pigment epithelium layer, diffuse loss of the nerve fiber layer, and an excavated optic nerve head with advanced-stage glaucoma. Imaging was performed using anterior segment optical coherence tomography to detect the iris configuration. In the heterochromic iris portion, the normal part of the iris showed a clear hyperreflective signal of the anterior border layer, while atrophy of the pigmented anterior border layer showed a hyporeflective area of the anterior surface resulting in reduced light absorption. Two mutations of the endothelin receptor type B gene were recognized in this study. The first (c.1111G>A on exon 7) leads to an amino acid change from glycine to serine at codon 371. Sanger verification revealed that this mutation is inherited from the mother. The other mutation (c.553G>A) leads to an amino acid change from valine to methionine at codon 185. Sanger verification showed that this mutation was inherited from the father.ConclusionWaardenburg syndrome shows a remarkable diversity in clinical presentation and morphology. This disease can also present with open-angle glaucoma. Sequencing analysis revealed two heterozygous mutations in the EDNRB gene in this patient, inherited from his mother and father, respectively. These two sites constitute a compound heterozygous variation.

Hearing characteristics and cochlear implant effects in children with Waardenburg syndrome: a case series.

BackgroundWaardenburg syndrome (WS) has high clinical and genetic heterogeneity. We aimed to investigate the clinical characteristics of children with WS, and to analyze the effect of cochlear implantation in children with WS who had severe sensorineural hearing loss.MethodsThe clinical characteristics of children with WS diagnosed and treated in the past 5 years in the Department of Otolaryngology, Shanghai Children’s Hospital were retrospectively analyzed. The 5 WS cases, including 2 males and 3 females, had bilateral severe sensorineural hearing loss. Cochlear implantation was performed between 8 and 21 months old. Audiology tests were conducted, including otoacoustic emissions (OAEs), auditory brainstem response (ABR), and multiple auditory steady-state evoked responses (ASSR). Preoperative computerized tomography (CT) and magnetic resonance imaging (MRI) were performed to evaluate the development of the inner ear and brain. All WS cases were evaluated for hearing and speech abilities before cochlear implantation and at 1 month, 6 months, 12 months, and 24 months after implantation.ResultsAmong the 5 cases, 3 were WS1, 1 was WS2, and 1 was WS4. All 5 cases received cochlear implantation, and postoperative CT showed that the implant position was good. The infant toddler meaningful auditory integration scale (IT-MAIS) and meaningful use of speech scale (MUSS) scores of all cases increased with hearing age, and IT-MAIS scores were lower than those of normal hearing children of the same age.ConclusionsChildren with WS usually have hearing loss. In WS cases with severe sensorineural hearing loss, early cochlear implantation can achieve better hearing and speech development.

A rare genetic disorder: Waardenburg syndrome

Waardenburg syndrome is an inherited autosomal dominant disorder consists group of rare genetic conditions. Mutation in the PAX3, MITF, SOX10 and SNAI2 genes are known as main cause for it. There are four types of Waardenburg syndrome differing in phenotypic characteristics are described. This syndrome is characterized by congenital deafness or some degree of hearing loss, different color of eyes with various degree of depigmentation of skin and hair, increased inter-canthal distance, Dystopia Canthorum. In this report a case has been discussed of finding a 30 years old male patient with Waardenburg syndrome.

Commentary: Waardenburg syndrome: Genetics and ocular features.

Commentary: Waardenburg syndrome: Genetics and ocular features.

Iris Heterochromia and Choroidal Hypopigmentation in Waardenburg Syndrome

A 10-year-old Black boy was referred for possible retinal hemorrhages. His visual acuity was 20/20 in both eyes. Examination revealed complete iris heterochromia, with one blue iris and one brown iris (Fig A). Fundus examination demonstrated diffuse areas of choroidal hypopigmentation (Fig B-C), notably also in the eye with normal iris pigment. OCT showed a loss of choroidal reflectivity in areas of hypopigmentation (Fig D). The patient did not have a white forelock or hearing loss, but had facial features of telecanthus and a wide nasal root, consistent with a diagnosis of Waardenburg syndrome (Magnified version of Fig A-D is available online at www.aaojournal.org).

Хірургічне лікування секвестрації легень у дітей

Pulmonary sequestration is a complex malformation of the lungs, which is based on a violation of the development of their bronchopulmonary and vascular components. The multifactorial nature of morphological and functional disorders is clinically manifested by respiratory distress syndrome and heart failure with a threat of a critical outcome for a newborn child, despite the sufficient development of the respiratory system as a whole. Purpose - optimization of diagnosis and treatment of lung sequestration in children based on the study of clinical and diagnostic data, as well as the results of surgical treatment. Materials and methods. The study included 18 patients aged from 8 days to 18 years, including newborns - 6, children from 1 to 12 months - 5, from 1 to 3 years - 3, from 7 to 9 years - 2 and from 15 to 18 years - 2. Median age was 4.5 months. Research methods included evaluation of clinical symptoms, chest X-ray, contrast-enhanced CT, and angiography. Prenatal diagnosis was carried out using ultrasonography and fetal MRI. In all cases, open surgical treatment was used. Results. Intrapulmonary sequestration was diagnosed in 13 (72.2%) patients, extrapulmonary - in 5 (27.8%), p=0.082. Left-sided localization in 11 (61.1%) patients, right-sided localization in 7 (38.9%) patients, р=0.3. Associated malformations had 9 (50%) patients: polycystic (n=4) or hypoplasia (n=2) of the lung, diaphragmatic hernia (n=3), pericardial defect (n=1), thoracic dystopia of the kidney (n=2), Waardenburg syndrome (n=1), ventricular septal defect (n=1), innominate artery tracheal compression (n=1). Symptomatic course was noted in 15 (83.3%) patients, asymptomatic - in 3 (16.7%) cases (p=0.021). Main symptoms were as follows: pulmonary bleeding, hemophthisis, respiratory and hemodynamic disorders, signs of inflammation. Lobectomy (n=8), atypical segmental lung resection (n=4) and transection of aberrant vessels (n=1) were performed for intrapulmonary sequestration, and sequestrectomy (n=4) for extrapulmonary sequestration. In cases of associated diaphragmatic hernia (n=3), simultaneous diaphragmatic plasty was performed, including using a non-free pericardial flap (n=1) or a PTFE patch (n=1), and in case of innominate artery compression of the trachea, aortopexy (n=1). In 17 (94.4%) cases, a positive result of surgical treatment was noted. Postoperative complications (intrathoracic bleeding) and lethality were observed in 1 (5.6%) case. Patients were examined in the long-term period from 2 months to 30 years after surgery. Conclusions. Surgical correction of pulmonary sequestration is appropriate as the diagnosis is made, mainly in the neonatal period. Given the complexity of the pathology, especially in the presence of associated malformations, and the expediency of early correction in the neonatal period, thoracotomy access should be preferred as safer for sequential division of arterial and then venous vessels, and for atypical segmental lung resection or lobectomy, depending on peculiarities of sequester. The presence of associated defects requires simultaneous correction. In the case of associated diaphragmatic hernia, autopericardial defect plastics or a synthetic patch are appropriate as an alternative to simple suturing. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Keywords: congenital malformations of the lungs, lung sequestration, surgical treatment, children.