Waardenburg Syndrome Type II, Associated with Atrial Septal Defect and Rocker Bottom Foot in a New Born – A Rare Case Presentation

Background: There are a number of syndromes with a combination of pigmentary abnormalities, hearing abnormalities and other defects. One among these pigmentary syndromes is waardenburg syndrome, which is further classified into four types. All these types show marked variability even within pedigrees. Case-Report: We are reporting a case of Waardenburg syndrome type 2, with an unusual presentation of atrial septal defect and rocker bottom foot. Conclusion: All clinicians on noticing, any child with white forelock of hair or heterochromia iris should get the child’s hearing tested and further systemic evaluation, at the first instance, because an early intervention for hearing impairment and other defects can improve the outcome of child. Family counselling is at-most important for these children with syndromes. We describe a unique case of Waardenburg syndrome type 2 with an unusual presentation of atrial septal defect and rocker bottom foot.

SOX10: 20 years of phenotypic plurality and current understanding of its developmental function

SOX10 belongs to a family of 20 SRY (sex-determining region Y)-related high mobility group box-containing (SOX) proteins, most of which contribute to cell type specification and differentiation of various lineages. The first clue that SOX10 is essential for development, especially in the neural crest, came with the discovery that heterozygous mutations occurring within and around SOX10 cause Waardenburg syndrome type 4. Since then, heterozygous mutations have been reported in Waardenburg syndrome type 2 (Waardenburg syndrome type without Hirschsprung disease), PCWH or PCW (peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, with or without Hirschsprung disease), intestinal manifestations beyond Hirschsprung (ie, chronic intestinal pseudo-obstruction), Kallmann syndrome and cancer. All of these diseases are consistent with the regulatory role of SOX10 in various neural crest derivatives (melanocytes, the enteric nervous system, Schwann cells and olfactory ensheathing cells) and extraneural crest tissues (inner ear, oligodendrocytes). The recent evolution of medical practice in constitutional genetics has led to the identification of SOX10 variants in atypical contexts, such as isolated hearing loss or neurodevelopmental disorders, making them more difficult to classify in the absence of both a typical phenotype and specific expertise. Here, we report novel mutations and review those that have already been published and their functional consequences, along with current understanding of SOX10 function in the affected cell types identified through in vivo and in vitro models. We also discuss research options to increase our understanding of the origin of the observed phenotypic variability and improve the diagnosis and medical care of affected patients.

Waardenburg syndrome type 2A in a large Iranian family with a novel MITF gene mutation

Background The characteristics of Waardenburg syndrome (WS) as a scarce heritable disorder are sensorineural hearing loss and deficits of pigmentation in the skin, hair, and eye. Here, clinical features and detection of the mutation in the MITF gene of WS2 patients are reported in a sizable Iranian family. Methods A man aged 28-years represented with symptoms of mild unilateral hearing loss (right ear), complete heterochromia iridis, premature graying prior to 30 years of age, and synophrys. In this research, there was a sizable family in Iran comprising three generations with seven WS patients and two healthy members. Whole exome sequencing was applied for proband for the identification of the candidate genetic mutations associated with the disease. The detected mutation in proband and investigated family members was validated by PCR-Sanger sequencing. Results A novel heterozygous mutation, NM_198159.3:c.1026dup p.(Asn343Glufs*27), in exon 9 of the MITF gene co-segregated with WS2 in the affected family members. The variant was forecasted as a disease-causing variant by the Mutation Taster. According to the UniProt database, this variant has been located in basic helix-loop-helix (bHLH) domain of the protein with critical role in DNA binding. Conclusions A frameshift was caused by a nucleotide insertion, c.1026dup, in exon 9 of the MITF gene. This mutation is able to induce an early termination, resulting in forming a truncated protein capable of affecting the normal function of the MITF protein. Helpful information is provided through an exactly described mutations involved in WS to clarify the molecular cause of clinical characteristics of WS and have a contribution to better genetic counseling of WS patients.

231 Outcomes of Cochlear Implantation in Patients with Waardenburg Syndrome: A Systematic Review and Narrative Synthesis

Aim This systematic review aims to establish outcomes of cochlear implantation (CI) in patients with a diagnosis of Waardenburg syndrome (WS). Method A systematic review and narrative synthesis were undertaken. Databases searched: Medline, PubMed, Embase, Web of Science, Cochrane Collection, and ClinicalTrials.gov. No limits placed on language or year of publication. A review conducted in accordance with the PRISMA statement. Results Searches identified 160 abstracts and 157 full texts. Of these, 22 studies met inclusion criteria reporting outcomes in 191 patients and at least 209 implants. Hearing outcomes of those receiving cochlear implantation were generally good. Five studies included genetic analysis of one or more of the participants. A total of 10 intra- or post-operative complications were reported. The methodological quality of included studies was modest, mainly comprising case reports and non-controlled case series with small cohort size. All studies were OCEBM grade III-IV. Conclusions Hearing outcomes following CI in Waardenburg syndrome are generally good with the majority of patients experiencing improvement in audiometry, speech perception, and speech intelligibility. Cochlear implant teams must use their clinical expertise to assess individual patients’ needs in order to perform cochlear implantation at the optimum age and provide thorough rehabilitation to maximise implantation benefits.

Case Report: A Novel Gross Deletion in PAX3 (10.26 kb) Identified in a Chinese Family With Waardenburg Syndrome by Third-Generation Sequencing

Waardenburg syndrome (WS) is a group of autosomal-dominant hereditary conditions with a global incidence of 1/42,000. WS can be categorized into at least four types: WS1–4, and these are characterized by heterochromia iridis, white forelock, prominent nasal root, dystopia canthorum, hypertrichosis of the medial part of the eyebrows, and deaf-mutism. WS3 is extremely rare, with a unique phenotype (upper limb abnormality). Heterozygous mutations of PAX3 are commonly associated with WS1, whereas partial or total deletions of PAX3 are often observed in WS3 cases. Deletions, together with insertions, translocations, inversions, mobile elements, tandem duplications, and complexes, constitute structural variants (SVs), which can be fully and accurately detected by third-generation sequencing (TGS), a new generation of high-throughput DNA sequencing technology. In this study, after failing to identify the causative gene by Sanger sequencing, SNP-array, and whole-exome sequencing (WES), we finally detected a heterozygous gross deletion of PAX3 (10.26kb, chr2: 223153899-223164405) in a WS family by TGS. Our description would enrich the genetic map of WS and help us to further understand this disease. Our findings also demonstrated the value of TGS in clinical genetics researches.

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

Waardenburg syndrome (WS) is an autosomal dominant inherited disorder that is characterized by sensorineural hearing loss and abnormal pigmentation. SOX10 is one of its main pathogenicity genes. The generation of patient-specific induced pluripotent stem cells (iPSCs) is an efficient means to investigate the mechanisms of inherited human disease. In our work, we set up an iPSC line derived from a WS patient with SOX10 mutation and differentiated into neural crest cells (NCCs), a key cell type involved in inner ear development. Compared with control-derived iPSCs, the SOX10 mutant iPSCs showed significantly decreased efficiency of development and differentiation potential at the stage of NCCs. After that, we carried out high-throughput RNA-seq and evaluated the transcriptional misregulation at every stage. Transcriptome analysis of differentiated NCCs showed widespread gene expression alterations, and the differentially expressed genes (DEGs) were enriched in gene ontology terms of neuron migration, skeletal system development, and multicellular organism development, indicating that SOX10 has a pivotal part in the differentiation of NCCs. It’s worth noting that, a significant enrichment among the nominal DEGs for genes implicated in inner ear development was found, as well as several genes connected to the inner ear morphogenesis. Based on the protein-protein interaction network, we chose four candidate genes that could be regulated by SOX10 in inner ear development, namely, BMP2, LGR5, GBX2, and GATA3. In conclusion, SOX10 deficiency in this WS subject had a significant impact on the gene expression patterns throughout NCC development in the iPSC model. The DEGs most significantly enriched in inner ear development and morphogenesis may assist in identifying the underlying basis for the inner ear malformation in subjects with WS.

Psychometric Properties of the Wechsler Intelligence Scale, WISC-IV for Deaf Intelligence with Wardenburg Syndrome and Level of Intelligence for Different Mental States

This study aimed to investigate the psychometric characteristics of the Wechsler-4 scale of the intelligence of deaf people with Waardenburg syndrome and the level of intelligence according to the mental state. To achieve the objectives of the study, a descriptive survey method was used. The sample of the study consisted of (17) students from all deaf schools in Jordan, whose ages ranged between (8-17) years, and (WISC-IV) was applied in sign language. Indicators are reached for Construct Validity (2.741 - 0.243). And indications for reliability, where the correlation coefficients ranged between (0.487 - 0.898). The results showed that there were no differences in the IQ level of deaf people with Waardenburg syndrome due to gender. The absence of differences in the IQ level of deaf people with Waardenburg syndrome is due to the mental state variable in favor of the deaf group of those with the borderline between Gifted and Superior, but the overall IQ level of the deaf person with Waardenburg syndrome is within the lower limits (IQ = 71), which is Learning Disability. There are also differences in the level of the sub-tests of the scale for deaf people with Waardenburg syndrome, as the (Cancellation) test was the highest score and then (coding) in second place. The study recommends including this syndrome as part of the hearing impairment categories. Studies have been carried out on the development of the functional section of the Wechsler-4 scale to suit the visual perception of deaf people with Waardenburg syndrome. Received: 27 February 2021 / Accepted: 5 June 2021 / Published: 8 July 2021