Waardenburg Syndrome

ABSTRACT

Auditory-pigmentary disorders result from the absence of melanocytes in the cochlea, skin, hair, and eyes. Waardenburg syndrome (WS) is one such autosomal dominant disorder that is characterized by congenital sensorineural hearing loss and pigmentation anomalies of neural crest-derived tissues. The clinical features of WS, including hearing loss, are not fully penetrant and interfamilial and intrafamilial variation in the phenotype is a common observation. A wide variety of unique mutations in at least six genes contribute to the phenotype in WS patients; however, the type and location of mutations have not been strongly correlated with the different clinical features that are expressed. Bilateral, congenital deafness is the most serious clinical feature expressed in the common types of WS and has been successfully habilitated through hearing aids or cochlear implants.

KEYWORDS

Waardenburg syndrome - hereditary deafness - pigmentation anomalies - dystopia canthorum - PAX3

REFERENCES

• 1 Waardenburg P J. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness.  Am J Hum Genet. 1951;  3 195-253
• 2 Arias S. Genetic heterogeneity in the Waardenburg syndrome.  Birth Defects Orig Artic Ser. 1971;  07 87-101
• 3 Arias S, Mota M. Apparent non-penetrance for dystopia in Waardenburg syndrome type I, with some hints on the diagnosis of dystopia canthorum.  J Genet Hum. 1978;  26 103-131
• 4 Farrer L A, Arnos K S, Asher Jr J H et al.. Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes.  Am J Hum Genet. 1994;  55 728-737
• 5 Hageman M J, Delleman J W. Heterogeneity in Waardenburg syndrome.  Am J Hum Genet. 1977;  29 468-485
• 6 Farrer L A, Grundfast K M, Amos J et al.. 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.  Am J Hum Genet. 1992;  50 902-913
• 7 Liu X Z, Newton V E, Read A P. Waardenburg syndrome type II: phenotypic findings and diagnostic criteria.  Am J Med Genet. 1995;  55 95-100
• 8 Goodman R M, Lewithal I, Solomon A, Klein D. Upper limb involvement in the Klein-Waardenburg syndrome.  Am J Med Genet. 1982;  11 425-433
• 9 Shah K N, Dalal S J, Desai M P, Sheth P N, Joshi N C, Ambani L M. White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: possible variant of Waardenburg syndrome.  J Pediatr. 1981;  99 432-435
• 10 Fraser G R. The Causes of Profound Deafness in Childhood: a Study of 3,535 Individuals with Severe Hearing Loss Present at Birth or of Childhood Onset. Baltimore, MD; The Johns Hopkins University Press 1976
• 11 Partington M W. Waardenburg's syndrome and heterochromia iridum in a deaf school population.  Can Med Assoc J. 1964;  90 1008-1017
• 12 Sellars S, Beighton P. The Waardenburg syndrome in deaf children in southern Africa.  S Afr Med J. 1983;  63 725-728
• 13 Newton V. Hearing loss and Waardenburg's syndrome: implications for genetic counselling.  J Laryngol Otol. 1990;  104 97-103
• 14 Fisch L. Deafness as part of an hereditary syndrome.  J Laryngol Otol. 1959;  73 355-382
• 15 Hageman M J. Audiometric findings in 34 patients with Waardenburg's syndrome.  J Laryngol Otol. 1977;  91 575-584
• 16 Oysu C, Baserer N, Tinaz M. Audiometric manifestations of Waardenburg's syndrome.  Ear Nose Throat J. 2000;  79 704-709
• 17 Liu X Z, Newton V E. Distortion product emissions in normal-hearing and low-frequency hearing loss carriers of genes for Waardenburg's syndrome.  Ann Otol Rhinol Laryngol. 1997;  106 220-225
• 18 Lonsbury-Martin B L, Martin G K, Whitehead M L. Distortion-product otoacoustic emissions in the normal hearing population. In: Robinette MS, Glattke TJ Otoacoustic Emissions: Clinical Applications. New York, NY; Thieme 1997: 83-109
• 19 Reynolds J E, Meyer J M, Landa B et al.. Analysis of variability of clinical manifestations in Waardenburg syndrome.  Am J Med Genet. 1995;  57 540-547
• 20 Oysu C, Oysu A, Aslan I, Tinaz M. Temporal bone imaging findings in Waardenburg's syndrome.  Int J Pediatr Otorhinolaryngol. 2001;  58 215-221
• 21 Migirov L, Henkin Y, Hildesheimer M, Muchnik C, Kronenberg J. Cochlear implantation in Waardenburg's syndrome.  Acta Otolaryngol. 2005;  125 713-717
• 22 Daneshi A, Hassanzadeh S, Farhadi M. Cochlear implantation in children with Waardenburg syndrome.  J Laryngol Otol. 2005;  119 719-723
• 23 Foy C, Newton V, Wellesley D, Harris R, Read A P. Assignment of the locus for Waardenburg syndrome type I to human chromosome 2q37 and possible homology to the Splotch mouse.  Am J Hum Genet. 1990;  46 1017-1023
• 24 Asher Jr J H, Morell R, Friedman T B. Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q.  Am J Hum Genet. 1991;  48 43-52
• 25 Ishikiriyama S, Tonoki H, Shibuya Y et al.. Waardenburg syndrome type I in a child with de novo inversion (2)(q35q37.3).  Am J Med Genet. 1989;  33 505-507
• 26 Asher Jr J H, Friedman T B. Mouse and hamster mutants as models for Waardenburg syndromes in humans.  J Med Genet. 1990;  27 618-626
• 27 Epstein D J, Vekemans M, Gros P. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3.  Cell. 1991;  67 767-774
• 28 Tassabehji M, Read A P, Newton V E et al.. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene.  Nature. 1992;  355 635-636
• 29 Baldwin C T, Hoth C F, Amos J A, da-Silva E O, Milunsky A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome.  Nature. 1992;  355 637-638
• 30 Morell R, Friedman T B, Moeljopawiro S, Hartono, Soewito, Asher Jr J H. A frameshift mutation in the HuP2 paired domain of the probable human homolog of murine Pax-3 is responsible for Waardenburg syndrome type 1 in an Indonesian family.  Hum Mol Genet. 1992;  1 243-247
• 31 Tassabehji M, Newton V E, Liu X Z et al.. The mutational spectrum in Waardenburg syndrome.  Hum Mol Genet. 1995;  4 2131-2137
• 32 Hoth C F, Milunsky A, Lipsky N, Sheffer R, Clarren S K, Baldwin C T. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).  Am J Hum Genet. 1993;  52 455-462
• 33 Zlotogora J, Lerer I, Bar-David S, Ergaz Z, Abeliovich D. Homozygosity for Waardenburg syndrome.  Am J Hum Genet. 1995;  56 1173-1178
• 34 Asher Jr J H, Sommer A, Morell R, Friedman T B. Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome.  Hum Mutat. 1996;  7 30-35
• 35 Tassabehji M, Newton V E, Read A P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.  Nat Genet. 1994;  8 251-255
• 36 Hodgkinson C A, Moore K J, Nakayama A et al.. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein.  Cell. 1993;  74 395-404
• 37 Hughes A E, Newton V E, Liu X Z, Read A P. A gene for Waardenburg syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12-p14.1  Nat Genet. 1994;  7 509-512
• 38 Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia A et al.. Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway.  Blood. 2002;  100 1274-1286
• 39 Sanchez-Martin M, Rodriguez-Garcia A, Perez-Losada J, Sagrera A, Read A P, Sanchez-Garcia I. SLUG (SNAI2) deletions in patients with Waardenburg disease.  Hum Mol Genet. 2002;  11 3231-3236
• 40 Hosoda K, Hammer R E, Richardson J A et al.. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.  Cell. 1994;  79 1267-1276
• 41 Baynash A G, Hosoda K, Giaid A et al.. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons.  Cell. 1994;  79 1277-1285
• 42 Southard-Smith E M, Kos L, Pavan W J. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model.  Nat Genet. 1998;  18 60-64
• 43 Puffenberger E G, Hosoda K, Washington S S et al.. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease.  Cell. 1994;  79 1257-1266
• 44 Attie T, Till M, Pelet A et al.. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease.  Hum Mol Genet. 1995;  4 2407-2409
• 45 Edery P, Attie T, Amiel J et al.. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).  Nat Genet. 1996;  12 442-444
• 46 Hofstra R M, Osinga J, Tan-Sindhunata G et al.. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome).  Nat Genet. 1996;  12 445-447
• 47 Pingault V, Bondurand N, Kuhlbrodt K et al.. SOX10 mutations in patients with Waardenburg-Hirschsprung disease.  Nat Genet. 1998;  18 171-173
• 48 Pingault V, Bondurand N, Lemort N et al.. A heterozygous endothelin 3 mutation in Waardenburg-Hirschsprung disease: is there a dosage effect of EDN3/EDNRB gene mutations on neurocristopathy phenotypes?.  J Med Genet. 2001;  38 205-209
• 49 Tachibana M, Kobayashi Y, Matsushima Y. Mouse models for four types of Waardenburg syndrome.  Pigment Cell Res. 2003;  16 448-454
• 50 Hibino H, Horio Y, Inanobe A et al.. An ATP-dependent inwardly rectifying potassium channel, KAB-2 (Kir4. 1), in cochlear stria vascularis of inner ear: its specific subcellular localization and correlation with the formation of endocochlear potential.  J Neurosci. 1997;  17 4711-4721
• 51 Yasumoto K, Yokoyama K, Shibata K, Tomita Y, Shibahara S. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene.  Mol Cell Biol. 1994;  14 8058-8070
• 52 Watanabe A, Takeda K, Ploplis B, Tachibana M. Epistatic relationship between Waardenburg syndrome genes MITF and PAX3.  Nat Genet. 1998;  18 283-286
• 53 Bondurand N, Pingault V, Goerich D E et al.. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.  Hum Mol Genet. 2000;  9 1907-1917
• 54 Goulding M D, Chalepakis G, Deutsch U, Erselius J R, Gruss P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis.  EMBO J. 1991;  10 1135-1147
• 55 Barber T D, Barber M C, Tomescu O, Barr F G, Ruben S, Friedman T B. Identification of target genes regulated by PAX3 and PAX3-FKHR in embryogenesis and alveolar rhabdomyosarcoma.  Genomics. 2002;  79 278-284
• 56 Pandya A, Xia X J, Landa B L et al.. Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?.  Hum Mol Genet. 1996;  5 497-502
• 57 Morell R, Spritz R A, Ho L et al.. Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA).  Hum Mol Genet. 1997;  6 659-664
• 58 Baldwin C T, Hoth C F, Macina R A, Milunsky A. Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature.  Am J Med Genet. 1995;  58 115-122
• 59 Morell R, Friedman T B, Asher Jr J H, Robbins L G. The incidence of deafness is non-randomly distributed among families segregating for Waardenburg syndrome type 1 (WS1).  J Med Genet. 1997;  34 447-452
• 60 DeStefano A L, Cupples L A, Arnos K S et al.. Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations.  Hum Genet. 1998;  102 499-506
• 61 Asher Jr J H, Harrison R W, Morell R, Carey M L, Friedman T B. Effects of Pax3 modifier genes on craniofacial morphology, pigmentation, and viability: a murine model of Waardenburg syndrome variation.  Genomics. 1996;  34 285-298
• 62 Schultz J M, Yang Y, Caride A J et al.. Modification of human hearing loss by plasma-membrane calcium pump PMCA2.  N Engl J Med. 2005;  352 1557-1564
• 63 Riazuddin S, Castelein C M, Ahmed Z M et al.. Dominant modifier DFNM1 suppresses recessive deafness DFNB26.  Nat Genet. 2000;  26 431-434
• 64 Noben-Trauth K, Zheng Q Y, Johnson K R. Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss.  Nat Genet. 2003;  35 21-23
• 65 Ikeda A, Zheng Q Y, Zuberi A R, Johnson K R, Naggert J K, Nishina P M. Microtubule-associated protein 1A is a modifier of tubby hearing (moth1).  Nat Genet. 2002;  30 401-405
• 66 Ng L, Rusch A, Amma L L et al.. Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor alpha gene.  Hum Mol Genet. 2001;  10 2701-2708
• 67 Kveton J, Balkany T J. Status of cochlear implantation in children. American Academy of Otolaryngology-Head and Neck Surgery Subcommittee on Cochlear implants.  J Pediatr. 1991;  118 1-7
• 68 Loundon N, Rouillon I, Munier N, Marlin S, Roger G, Garabedian E N. Cochlear implantation in children with internal ear malformations.  Otol Neurotol. 2005;  26 668-673
• 69 Mylanus E A, Rotteveel L J, Leeuw R L. Congenital malformation of the inner ear and pediatric cochlear implantation.  Otol Neurotol. 2004;  25 308-317
• 70 Buchman C A, Copeland B J, Yu K K, Brown C J, Carrasco V N, Pillsbury III H C. Cochlear implantation in children with congenital inner ear malformations.  Laryngoscope. 2004;  114 309-316