Waardenburg Syndrome (Klein Syndrome)

Rare, autosomal dominant disease with variable penetrance and several known clinical types. Characteristics may include depigmentation of the hair and skin, congenital deafness, heterochromia iridis, medial eyebrow hyperplasia, hypertrophy of the nasal root, and especially dystopia canthorum. The underlying cause may be defective development of the neural crest (neurocristopathy). Waardenburg's syndrome may be closely related to piebaldism. Klein-Waardenburg Syndrome refers to a disorder that also includes upper limb abnormalities.

Also Known As:

Klein Syndrome; Klein's Syndrome; Waardenburg Syndrome Type 1; Waardenburg Syndrome Type 3; Waardenburg Syndrome with Dystopia Canthorum; Waardenburg Syndrome with Upper Limb Anomalies; Waardenburg Syndrome, Type 1; Waardenburg Syndrome, Type 3; Waardenburg Syndrome, Type III; Waardenburg's Syndrome Type 1; Waardenburg-Klein Syndrome; White Forelock (Poliosis) Syndrome with Multiple Congenital Malformations; Klein Waardenburg Syndrome; Kleins Syndrome; Syndrome, Klein; Syndrome, Klein's; Syndrome, Klein-Waardenburg; Syndrome, Waardenburg; Syndrome, Waardenburg's; Syndrome, Waardenburg-Klein; Waardenburg Klein Syndrome; Waardenburgs Syndrome; Klein-Waardenburg Syndrome; Waardenburg's Syndrome

Networked: 115 relevant articles (0 outcomes, 13 trials/studies)

Disease Context: Research Results

Congenital, Hereditary, and Neonatal Diseases and Abnormalities: 933
- Congenital Abnormalities: 25723
  - Multiple Abnormalities: 211
    - Waardenburg Syndrome: 115

Related Diseases

1.	Deafness (Deaf Mutism)
2.	Hearing Loss (Hearing Impairment)
3.	Sensorineural Hearing Loss
4.	Hypopigmentation (Hypomelanosis)
5.	Hirschsprung Disease (Hirschsprung's Disease)

Experts

1.	Feng, Yong: 5 articles (01/2022 - 02/2015)
2.	Zhang, Hua: 4 articles (05/2018 - 02/2015)
3.	Guo, Weiwei: 3 articles (06/2021 - 01/2016)
4.	Yang, Shiming: 3 articles (06/2021 - 01/2016)
5.	Chen, Hongsheng: 3 articles (08/2017 - 02/2015)
6.	Fisher, David E: 3 articles (01/2012 - 11/2003)
7.	Corry, Gareth N: 3 articles (09/2010 - 12/2005)
8.	Underhill, D Alan: 3 articles (09/2010 - 12/2005)
9.	Pavan, William J: 3 articles (07/2008 - 02/2006)
10.	Ma, Jing: 2 articles (05/2022 - 06/2016)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Waardenburg Syndrome:

1.	Proteins (Proteins, Gene)FDA Link 02/01/2015 - "To study the exogenous expression and subcellular localization of wild type (WT) and mutant SOX10 proteins in vitro through generation of expression plasmids in order to reveal the pathogenesis of Waardenburg syndrome (WS). " 08/10/2017 - "The mutation can affect the subcellular distribution of MITF proteins in vitro, which may shed light on the molecular mechanism of Waardenburg syndrome caused by mutations of the MITF gene." 08/14/2015 - "Mutations in PAX3 are associated with Waardenburg syndrome (WS), but the mechanism of how mutant PAX3 proteins cause WS remains unclear. " 01/01/2013 - "The mutation causes V263G amino-acid substitution in the homeodomain of the PAX3 protein, which represents the 45(th) residue of helix 3. We identified a novel missense c.788T>G mutation in PAX3 in a family with Waardenburg syndrome with intrafamilial phenotypic heterogeneity." 10/01/1993 - "Such mutations have been shown previously to be the cause of mouse developmental mutants (undulated, Splotch, and Small eye) and human syndromes (Waardenburg's syndrome and aniridia) and may thus differentially affect the regulation of target genes by the mutated Pax protein."
2.	Microphthalmia-Associated Transcription FactorIBA 05/01/2018 - "Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. " 07/01/2003 - "The Wh(V203) mutation in the Syrian hamster affects the same functional domains of the Mitf transcription factor as the human R124X mutation, causing human Waardenburg syndrome type II. Therefore, the Wh(V203) hamster mutant provides a novel model for this particular syndrome." 11/01/2017 - "Human Waardenburg syndrome 2A (WS2A) is a dominant hearing loss (HL) syndrome caused by mutations in the microphthalmia-associated transcription factor (MITF) gene. " 12/01/2015 - "To study the role of dysfunction of nuclear localization signals (NLS) of MITF protein in the pathogenesis of Waardenburg syndrome. " 04/01/2008 - "Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders."
3.	DNA (Deoxyribonucleic Acid)IBA 10/01/2019 - "Genomic DNA was extracted from fifteen individuals of a Saudi family segregating Waardenburg syndrome. " 10/01/1997 - "Reciprocal effect of Waardenburg syndrome mutations on DNA binding by the Pax-3 paired domain and homeodomain." 01/01/1997 - "Genomic DNA from probands of various Waardenburg syndrome (WS) families were PCR-amplified using primers flanking the 8 exons of PAX3. " 06/04/2021 - "In this study, based on a pig model that carries the c.740T>C (L247S) mutation in MITF with an inheritance pattern and clinical pathology that mimics Waardenburg syndrome 2A (WS2A), we corrected the point mutation by the CRISPR-Cas9 system in the mutant fibroblast cells using single-stranded oligodeoxynucleotide (ssODN) and long donor plasmid DNA as the repair template. " 02/17/2009 - "The structure elucidates the role of serine 50 in selection of the CG sequence immediately 3' of the TAAT motif by PAX class homeodomains and provides insights into the molecular mechanisms by which certain Waardenburg syndrome-associated missense mutations could destabilize the fold of the PAX3 homeodomain whereas others could affect its interaction with DNA."
4.	placental alkaline phosphataseIBA 05/01/1992 - "Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal portion of chromosome 2q, near the ALPP locus. " 05/01/1992 - "Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium." 06/01/1990 - "We have demonstrated close linkage between the locus for the autosomal dominant Waardenburg syndrome type I and the placental alkaline phosphatase locus on chromosome 2q37. " 01/01/1993 - "Multilocus linkage analysis has suggested that the Waardenburg syndrome type 1 (WS1) locus is flanked by placental alkaline phosphatase (ALPP) and fibronectin 1 (FN1). "
5.	Endothelin Receptors (Endothelin Receptor)IBA 01/01/2019 - "The genovariation of endothelin receptor type B (EDNRB) was identified in a Chinese family with Waardenburg syndrome type I (WS1) in the present study. " 02/01/2006 - "Mutations in the transcription factor Sox10 or Endothelin Receptor B (Ednrb) result in Waardenburg Syndrome Type IV (WS-IV), which presents with deficiencies of neural crest derived melanocytes (hypopigmentation) and enteric ganglia (hypoganglionosis). "
6.	Nuclear Localization Signals (Nuclear Localization Signal)IBA 12/01/2015 - "To study the role of dysfunction of nuclear localization signals (NLS) of MITF protein in the pathogenesis of Waardenburg syndrome. "
7.	OligodeoxyribonucleotidesIBA 06/04/2021 - "In this study, based on a pig model that carries the c.740T>C (L247S) mutation in MITF with an inheritance pattern and clinical pathology that mimics Waardenburg syndrome 2A (WS2A), we corrected the point mutation by the CRISPR-Cas9 system in the mutant fibroblast cells using single-stranded oligodeoxynucleotide (ssODN) and long donor plasmid DNA as the repair template. "
8.	12S ribosomal RNAIBA 01/01/2022 - "The results in the limited samples of this study show that Usher and Waardenburg syndrome-related genes account for a major proportion are strongly associated with Chinese Han hearing loss patients negative for GJB2, SLC26A4, and mitochondrial 12S rRNA, followed by STRC resulting in mild to moderate deafness."
9.	Transcription Factors (Transcription Factor)IBA 07/01/2011 - "Novel splice mutation in microthalmia-associated transcription factor in Waardenburg Syndrome." 06/01/2008 - "The transcription factor paired box 3 (Pax3) is expressed by multipotent neural crest precursors and is implicated in neural crest disorders in humans such as Waardenburg syndrome. " 10/15/2003 - "Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. " 07/01/2000 - "Waardenburg syndrome (WS) is associated with neural crest-derived melanocyte deficiency caused by mutations in either one of three transcription factors: MITF, PAX3, and SOX10. " 07/01/2000 - "Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3."
10.	Nonsense Codon (Nonsense Mutation)IBA 06/01/2016 - "Waardenburg syndrome type II in a Chinese patient caused by a novel nonsense mutation in the SOX10 gene." 01/05/2007 - "Nonsense mutations in the PAX3 gene cause Waardenburg syndrome type I in two Chinese patients." 04/01/2021 - "Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. " 04/01/2021 - "A novel SOX10 nonsense mutation in a patient with Kallmann syndrome and Waardenburg syndrome." 01/01/2018 - "A case report of reversible generalized seizures in a patient with Waardenburg syndrome associated with a novel nonsense mutation in the penultimate exon of SOX10."

Therapies and Procedures

1.	Cochlear Implantation 08/01/2023 - "All studies were OCEBM grade III-IV. Cochlear implantation in congenitally deafened children with Waardenburg Syndrome is a well-established intervention as a method of auditory rehabilitation. " 08/01/2017 - "The aim of this study was to present the surgical findings of children with Waardenburg syndrome (WS) and investigate speech development after cochlear implantation in this unique group of patients. " 08/01/2011 - "The objective of this study was a state-of-the-art analysis of cochlear implantation in patients with Waardenburg syndrome (WS). " 12/01/2023 - "Cochlear implantation in Waardenburg syndrome: Systematic review and meta-analysis." 08/01/2023 - "Outcomes of Cochlear implantation in early-deafened patients with Waardenburg syndrome: A systematic review and narrative synthesis."
2.	Cochlear Implants (Cochlear Implant) 07/01/2013 - "Children who were diagnosed with Waardenburg syndrome and who received a multichannel cochlear implant between March 1999 and July 2012 were included in the study. " 01/01/2010 - "This study provides the first description of isolated cerebellar dysplasia associated with Waardenburg syndrome (WS) and includes a review of cochlear implant outcomes in 42 WS patients. " 07/01/2022 - "Hearing characteristics and cochlear implant effects in children with Waardenburg syndrome: a case series." 10/01/2015 - "Children with Waardenburg syndrome usually require anaesthesia for the cochlear implant operation in early age. " 07/01/2013 - " Despite the heterogeneity of the group, patients with Waardenburg syndrome who received cochlear implants were found to have hearing thresholds that allowed access to speech sounds. "
3.	Therapeutics 01/01/2022 - "Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome." 01/01/2020 - ": 4H: Hypomyelination, hypogonadotropic hypogonadism and hypodontia; AAV: Adeno-associated virus; AD: autosomal dominant; AGS: Aicardi-Goutieres syndrome; ALSP: Axonal spheroids and pigmented glia; APGBD: Adult polyglucosan body disease; AR: autosomal recessive; ASO: Antisense oligonucleotide therapy; AxD: Alexander disease; BAEP: Brainstem auditory evoked potentials; CAA: Cerebral amyloid angiopathy; CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy; CARASIL: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CGH: Comparative genomic hybridization; ClC2: Chloride Ion Channel 2; CMTX: Charcot-Marie-Tooth disease, X-linked; CMV: Cytomegalovirus; CNS: central nervous system; CRISP/Cas9: Clustered regularly interspaced short palindromic repeat/CRISPR-associated 9; gRNA: Guide RNA; CTX: Cerebrotendinous xanthomatosis; DNA: Deoxyribonucleic acid; DSB: Double strand breaks; DTI: Diffusion tensor imaging; FLAIR: Fluid attenuated inversion recovery; GAN: Giant axonal neuropathy; H-ABC: Hypomyelination with atrophy of basal ganglia and cerebellum; HBSL: Hypomyelination with brainstem and spinal cord involvement and leg spasticity; HCC: Hypomyelination with congenital cataracts; HEMS: Hypomyelination of early myelinated structures; HMG CoA: Hydroxy methylglutaryl CoA; HSCT: Hematopoietic stem cell transplant; iPSC: Induced pluripotent stem cells; KSS: Kearns-Sayre syndrome; L-2-HGA: L-2-hydroxy glutaric aciduria; LBSL: Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate; LCC: Leukoencephalopathy with calcifications and cysts; LTBL: Leukoencephalopathy with thalamus and brainstem involvement and high lactate; MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; MERRF: Myoclonic epilepsy with ragged red fibers; MLC: Megalencephalic leukoencephalopathy with subcortical cysts; MLD: metachromatic leukodystrophy; MRI: magnetic resonance imaging; NCL: Neuronal ceroid lipofuscinosis; NGS: Next generation sequencing; ODDD: Oculodentodigital dysplasia; PCWH: Peripheral demyelinating neuropathy-central-dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschprung disease; PMD: Pelizaeus-Merzbacher disease; PMDL: Pelizaeus-Merzbacher-like disease; RNA: Ribonucleic acid; TW: T-weighted; VWM: Vanishing white matter; WES: whole exome sequencing; WGS: whole genome sequencing; X-ALD: X-linked adrenoleukodystrophy; XLD: X-linked dominant; XLR: X-linked recessive."
4.	Telescopes 09/01/1965 - "A pedigree of binocular heterochromia iridis associated with other anomalies (Waardenburg-Klein syndrome)."
5.	Iridectomy 01/01/1998 - "Evaluation of 4-month-old girl who presented with congenital cataracts revealed heterochromia iridis, fundus hypopigmentation, residual white forelock and sensory neural hearing loss--findings consistent with Waardenburg syndrome type II. Bilateral peripheral iridectomies performed at lensectomy provided tissue for evaluation. "