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ABSTRACT: Eight patients with Waardenburg's syndrome (WS) with normal hearing and 3 additional patients exhibiting a low-frequency hearing loss were tested for the level of the acoustic distortion product 2f1-f2 by means of the Otodynamics Distortion Product Analyser (ILO92). Wide notches in distortion product otoacoustic emissions (DPOAEs) between 1,000 and 3,000 Hz were found in 7 (12 ears, 87.5%) examined patients with normal audiograms, which was a significantly higher rate than that found in the control group (10%). The 3 patients with low-frequency hearing loss a gave a consistent pattern in audiometric configuration shown by both pure tone audiograms and DPOAEs. It is concluded from these initial results that DPOAEs may be a useful approach to identifying subclinical pathologic aberrations in the inner ear in WS patients, and may be a predictor of low-frequency sensorineural hearing loss.
The Annals of otology, rhinology, and laryngology 04/1997; 106(3):220-5. · 1.05 Impact Factor
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ABSTRACT: One hundred and thirty-four families or individuals with auditory-pigmentary syndromes such as Waardenburg syndrome (WS) or probable neurocristopathies were screened for mutations in the PAX3 and MITF genes. PAX3 mutations were found in 20/25 families with definite Type 1 WS and 1/2 with Type 3 WS, but in none of 23 with definite Type 2 WS or 36 with other neurocristopathies. The PAX3 mutations included substitutions of conserved amino acids in the paired domain or the homeodomain, splice-site mutations, nonsense mutations and frame-shifting insertions or deletions. No phenotype-genotype correlations were noted within WS1 families. With MITF, mutations likely to affect protein function were found in seven families, five of which had definite Type 2 WS. We conclude that Type 1 and Type 3 WS are allelic and are normally caused by loss of function mutations in PAX3; that Type 2 WS is heterogeneous, with about 20% of cases caused by mutations in MITF, and that individuals with auditory, pigmentary or neural crest syndromes which do not fit stringent definitions of Waardenburg syndrome are unlikely to have mutations in either the PAX3 or MITF genes. The molecular pathology of MITF/microphthalmia mutations appears to be different in humans and mice, with gene dosage having more significant effects in humans than in the mouse.
Human Molecular Genetics 12/1995; 4(11):2131-7. · 7.64 Impact Factor
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ABSTRACT: The Waardenburg syndrome (WS) consists of at least two distinct autosomal dominant hereditary disorders. WS Type I has been mapped to the distal part of chromosome 2q and the gene identified as PAX3. Other gene(s) are responsible for WS Type II. Mapping WS Type II requires accurate diagnosis within affected families. To establish diagnostic criteria for WS Type II, 81 individuals from 21 families with Type II WS were personally studied, and compared with 60 personally studied patients from 8 families with Type I and 253 cases of WS (Type I or II) from the literature. Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II. Both were more common in Type II than in Type I. Other clinical manifestations, such as white forelock and skin patches, were more frequent in Type I. We estimate the frequency of phenotypic traits and propose diagnostic criteria for WS Type II. In practice, a diagnosis of WS Type II can be made with confidence given a family history of congenital hearing loss and pigmentary disorders, where individuals have been accurately measured for ocular distances to exclude dystopia canthorum.
American Journal of Medical Genetics 02/1995; 55(1):95-100.
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ABSTRACT: Waardenburg syndrome (WS), an autosomal dominant syndrome of hearing loss and pigmentary disturbances, comprises at least two separate conditions. WS type 1 is normally caused by mutations in PAX3 located at chromosome 2q35 and is distinguished clinically by minor facial malformations. We have now located a gene for WS type 2. Two families show linkage to a group of microsatellite markers located on chromosome 3p12-p14.1. D3S1261 gave a maximum lod score of 6.5 at zero recombination in one large Type 2 family. In a second, smaller family the adjacent marker D3S1210 gave a lod of 2.05 at zero recombination. Interestingly, the human homologue (MITF) of the mouse microphthalmia gene, a good candidate at the phenotypic level, has recently been mapped to 3p12.3-p14.4.
Nature Genetics 09/1994; 7(4):509-12. · 35.53 Impact Factor
