Analysis of variability of clinical manifestations in Waardenburg syndrome

Abstract

Expression of clinical findings of Waardenburg syndrome type 1 (WS1) and type 2 (WS2) is extremely variable. Using our collection of 26 WS1 and 8 WS2 families, we analyzed the occurrence, severity, and symmetry of clinical manifestations associated with WS. We found significant differences between WS1 and WS2 in deafness, and in pigmentary and craniofacial anomalies. Factor analysis was used to identify manifestations which covaried, resulting in 2 orthogonal factors. Since mean factor scores were found to differ when compared between WS1 and WS2, we suggest that these factors could be useful in distinguishing WS types. We found that the WS gene was transmitted from mothers more often than from fathers. We also extensively examined the W-Index, a continuous measure of dystopia canthorum. Our data suggest that use of the W-Index to discriminate between affected WS1 and WS2 individuals may be problematic since 1) ranges of W-Index scores of affected and unaffected individuals overlapped considerably within both WS1 and WS2, and 2) a considerable number of both affected and unaffected WS2 individuals exhibited W-index scores consistent with dystopia canthorum. Misclassification of families may have implications for risk assessment of deafness, since WS2 families have been reported to have greater incidence of deafness, as confirmed in our study.

Screening program for Waardenburg syndrome in Colombia: Clinical definition and phenotypic variability

“…Arias and Silan claimed that type 2 was more common than type 1 [Arias, 1971;Silan et al, 2006], while the majority of reports presented more cases of WS1 [Pardono et al, 2003]. In the present study, the distribution of our patients was in agreement with Arias' and Silan' studies, since we also found more type 2 cases (62.1% WS2 vs. 37.9% WS1) than others where the frequency of type 1 was higher [Reed et al, 1967;Liu et al, 1995;Reynolds et al, 1995]. This difference may be due to ascertainment bias, since we were looking for WS patients among educational centers for the deaf children and deafness is known to be more common in WS2.…”

“…Since the phenotypic expression of the syndrome is extremely variable, clinical diagnostic criteria have been established by an international WS consortium [Liu et al, 1995;Reynolds et al, 1995], which includes major and minor clinical manifestations [Arias, 1971;McKusick, 1994;Liu et al, 1995;Reynolds et al, 1995;Pardono et al, 2003]. …”

Analysis of Locus Heterogeneity in Waardenburg Syndrome Types 1 and 2 Using Highly Informative Microsatellite Markers

“…Allelic heterogeneity at PAX3 may also influence clinical features, just as mutations are now known at the cystic fibrosis locus which lead to congenital absence of the vas deferens with out any other features of cystic fibrosis [36], Identification of additional WS genes will lead to a better understanding of the clinical variability which characterizes this disorder. Associated studies from our laboratory have found differences in the occurrence, severity, and laterality of some of the common clinical symptoms among WS1 PAX3-linked and WS2-affected individuals [37], A finding of that study which is particularly relevant to the present report is the variability in the expres sion of dystopia among affected individuals in PAX3-linked families. These data, as well as data for other families [38], show that some clearly affected members of type 1 families do not exhibit dystopia canthorum (as measured by the W-index).…”

„Auditory pigmentary syndromes“ — klinische Erscheinungsbilder und genetischer Hintergrund

“…Obwohl eine hohe Penetranz angegeben wird, sind die klinischen Charakteristika bei den betroffenen Individuen sogar innerhalb einer Familie sehr unterschiedlich [3,8,12,14]. So auch in unserer Familie: während bei der Mutter (H-9) lediglich der fundoskopische Befund auffällig war (fleckige Hyper-und Depigmentierungen der Peripherie), waren bei den zwei betroffenen Söhnen (11I-4, I11-5) ausgeprägte Pigmentstörungen der Augen und schwere Hörstörun-gen vorhanden.…”

“…Bei WS Typ 2 betroffenen Individuen wurde eine besonders hohe Inzidenz von Taubheit, zumeist beidseitig auftretend, festgestellt [8,14,15,24]. Auch diese Hörstörung kann erklärt werden durch ein lokales, umschriebenes Fehlen der Melanozyten in der Stria vascularis der Cochlea [13].…”